Forebrain neurons that project to the gustatory parabrachial nucleus in rat lack glutamic acid decarboxylase.
Evidence suggests that GABA might mediate the inhibitory influence of centrifugal inputs on taste-evoked responses in the parabrachial nucleus (PBN). Previous studies show that activation of the gustatory cortex (GC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH) inhibits PBN taste responses, GABAergic neurons are present in these forebrain regions, and GABA reduces the input resistance of PBN neurons. The present study investigated the expression of glutamic acid decarboxylase immunoreactivity (GAD_67 ir) in GC, BNST, CeA, and LH neurons that project to the PBN in rats. After anesthesia (50 mg/kg ip Nembutal), injections of the retrograde tracer Fluorogold (FG) were made in the physiologically defined gustatory PBN. Brain tissue containing the above forebrain structures was processed and examined for FG and GAD_67 ir. Similar to previous studies, each forebrain site contained retrogradely labeled neurons. Our results suggest further that the major source of input to the PBN taste region is the CeA (608 total cells) followed by GC (257 cells), LH (106 cells), and BNST (92 cells). This suggests a differential contribution to centrifugal control of PBN taste processing. We further show that despite the presence of GAD_67 neurons in each forebrain area, colocalization was extremely rare, occurring only in 3 out of 1,063 FG-labeled cells. If we assume that the influence of centrifugal input is mediated by direct projections to the gustatory region of the PBN, then GABAergic forebrain neurons apparently are not part of this descending pathway.


Improved measurement of two-mode quantum correlations using a phase-sensitive amplifier.
We demonstrate the ability of a phase-sensitive amplifier (PSA) to pre-amplify a selected quadrature of one mode of a two-mode squeezed state in order to improve the measurement of two-mode quantum correlations that exist before degradation due to optical and detection losses. We use four-wave mixing (4WM) in 85Rb vapor to generate bright beams in a two-mode squeezed state. One of these two modes then passes through a second 4WM interaction in a PSA configuration to noiselessly pre-amplify the desired quadrature of the mode before loss is intentionally introduced. We demonstrate an enhancement in the measured degree of intensity correlation and intensity-difference squeezing between the two modes.


Levels of consciousness in volunteers breathing sub-MAC concentrations of isoflurane.
Eight volunteers inhaled isoflurane in concentrations of 0.1, 0.2 and 0.4 MAC, and 100% oxygen as control in separate sessions more than 1 week apart. When the end-expiratory isoflurane concentration was stable, response to verbal commands was tested, and the subjects were read 30 words in two lists. Response to the commands was impaired at 0.1 MAC in three subjects and lost at 0.2 MAC in two subjects. No subject responded at 0.4 MAC. When the subjects were questioned 1 h after exposure, memory of response to commands was lost also at these concentrations. Frequently, those who responded to the command "open your eyes" failed to remember having done so; non-responders remembered nothing. At the time of that test, at 0.4 MAC, five of eight subjects had no eyelash reflex. Both recall and recognition of neutral words was lost at 0.2 MAC and greater, but the effect of attention was demonstrated by the memory of a "shock" word by four of eight subjects at 0.2 MAC.


Socioeconomic differentials in mortality risk among men screened for the Multiple Risk Factor Intervention Trial: I. White men.
This study examined socioeconomic differentials in risk of death from a number of specific causes in a large cohort of White men in the United States. For 300 685 White men screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, data were collected on median income of White households in the zip code of residence, age, cigarette smoking, blood pressure, serum cholesterol, previous myocardial infarction, and drug treatment for diabetes. The 31 737 deaths that occurred over the 16-year follow-up period were grouped into specific causes and related to median White family income. There was an inverse association between age- adjusted all-cause mortality and median family income. There was no attenuation of this association over the follow-up period, and the association was similar for the 22 clinical centers carrying out the screening. The gradient was seen for many-but not all-of the specific causes of death. Other risk factors accounted for some of the association between income and coronary heart disease and smoking-related cancers. Socioeconomic position, as measured by median family income of area of residence, is an important determinant of mortality risk in White men.


[Intrafamilial contagion with the hepatitis B virus].
A study of the intrafamilial transmission of the hepatitis B virus (HBV) and its relationship with the viral replication and epidemiological factors. The intrafamilial transmission of 106 chronic carriers of HBV was evaluated: 79 were asymptomatic carriers (AC) and 27 had chronic liver disease (CLD). Overall 347 relatives of the first group individuals and 112 of the second group were investigated. In the index cases, all HBV markers were investigated, and also DNA-HBV in those with CLD. In the relatives, HBsAg, HBsAc and HBcAc were investigated. Also, a survey to evaluate the influence of socioeconomic and cultural factors was also carried out. The prevalence of markers was significantly higher in the relatives of patients with CLD (HBcAg, HBcAc and evidence of contact) followed by AC and controls. The most infective relation in AC was that of other contacts with significant differences from the mother-child relationship (HBsAc p less than 0.003, HBcAc p less than 0.01, and evidence of contact p less than 0.001). By contrast, in CLD the most infective relation was mother-child. The mother-child relation was more infective than the father-child one (HBsAg p less than 0.05, HBcAc p less than 0.03, and evidence of contact p less than 0.02). Regarding viral replication, it was found that the HBeAg and DNA positive patients were more infective. The prevalence of HBcAc and the evidence of contact increased with the time of living together of spouses. Finally, it can be stated in a general sense that, according to the results of the survey, the socioeconomic factors have a small influence on the familial transmission. The relatives of HBV carriers, particularly in the case of HC with high replication, have a high risk of transmission. Thus, their investigation and subsequent vaccination is mandatory.


Interpreting radiographs 6: Radiology of the equine head (Part 2).
The value of radiology as part of an examination of the equine head is emphasised and the radiological appearances of more commonly occurring conditions are described. Even the normal anatomy of this complex site is subject to great variation and the aspiring radiologist should, therefore, have a good knowledge of the possible normal variations. A flexible approach must be used rather than a limitation to one or two ritual projections. The use of contrast media, wherever it might be useful, is advocated so that the maximum amount of information may be obtained from each examination. Finally, emphasis is laid on the fallibility of radiology when used in isolation and its use to complement other investigative procedures, such as endoscopy, is encouraged.


Optimized Cultivation and Syntrophic Relationship of Anaerobic Benzene-Degrading Enrichment Cultures under Methanogenic Conditions.
Current challenges in the anaerobic bioremediation of benzene are the lack of capable cultures and limited knowledge on the biodegradation pathway. Under methanogenic conditions, benzene may be mineralized by syntrophic interactions between microorganisms, which are poorly understood. The present study developed an optimized formula for anoxic medium to successfully promote the growth of the putative benzene degrader Deltaproteobacterium Hasda-A and enhance the benzene degradation activity of methanogenic enrichment cultures. Within 70 d of incubation, the benzene degradation activity and relative abundance of Hasda-A in cultures in the new defined medium increased from 0.5 to >3 mg L-1 d-1 and from 2.5% to >17%, respectively. Together with Hasda-A, we found a strong positive relationship between the abundances of superphylum OD1 bacteria, three methanogens (Methanoregula, Methanolinea, and Methanosaeta) and benzene degradation activity. The syntrophic relationship between these microbial taxa and Hasda-A was then demonstrated in a correlation analysis of longitudinal data. The involvement of methanogenesis in anaerobic benzene mineralization was confirmed by inhibition experiments. The high benzene degradation activity and growth of Hasda-A were quickly recovered in successive dilutions of enrichment cultures, proving the feasibility of using the medium developed in the present study to produce highly capable cultures. The present results will facilitate practical applications in bioremediation and research on the molecular mechanisms underlying benzene activation and syntrophic interactions in benzene mineralization.


Ground-state dioxygen undergoes metal-free [3 + 2]-annulations with allenes and nitrosoarenes under ambient conditions.
The cycloadditions of molecular dioxygen with neutral π-bond motifs rely heavily on singlet-state 1O2, whereas ground state 3O2 is chemically inactive. Here we report novel [3 + 2]-annulations among ground-state 3O2 (1 bar), allenes, and nitrosoarenes at low temperatures, efficiently yielding dioxygen-containing oxacycles. With less hindered 1-arylallene derivatives, these dioxygen species undergo skeletal rearrangement to 3-hydroxy-1-ketonyl-2-imine oxides. These cycloadditions represent valuable one-pot O,N,O-trifunctionalizations of allenes. Our EPR experiments confirm the presence of 1,4-diradical intermediates from an allene/nitrosoarene mixture, which manifest the hidden diradical properties of nitrosoarenes.


Architecture of a nascent viral fusion pore.
Enveloped viruses use specialized protein machinery to fuse the viral membrane with that of the host cell during cell invasion. In influenza virus, hundreds of copies of the haemagglutinin (HA) fusion glycoprotein project from the virus surface. Despite intensive study of HA and its fusion activity, the protein's modus operandi in manipulating viral and target membranes to catalyse their fusion is poorly understood. Here, the three-dimensional architecture of influenza virus-liposome complexes at pH 5.5 was investigated by electron cryo-tomography. Tomographic reconstructions show that early stages of membrane remodeling take place in a target membrane-centric manner, progressing from punctate dimples, to the formation of a pinched liposomal funnel that may impinge on the apparently unperturbed viral envelope. The results suggest that the M1 matrix layer serves as an endoskeleton for the virus and a foundation for HA during membrane fusion. Fluorescence spectroscopy monitoring fusion between liposomes and virions shows that leakage of liposome contents takes place more rapidly than lipid mixing at pH 5.5. The relation of 'leaky' fusion to the observed prefusion structures is discussed.


Evidence of a metabolic memory to early-life dietary restriction in male C57BL/6 mice.
Dietary restriction (DR) extends lifespan and induces beneficial metabolic effects in many animals. What is far less clear is whether animals retain a metabolic memory to previous DR exposure, that is, can early-life DR preserve beneficial metabolic effects later in life even after the resumption of ad libitum (AL) feeding. We examined a range of metabolic parameters (body mass, body composition (lean and fat mass), glucose tolerance, fed blood glucose, fasting plasma insulin and insulin-like growth factor 1 (IGF-1), insulin sensitivity) in male C57BL/6 mice dietary switched from DR to AL (DR-AL) at 11 months of age (mid life). The converse switch (AL-DR) was also undertaken at this time. We then compared metabolic parameters of the switched mice to one another and to age-matched mice maintained exclusively on an AL or DR diet from early life (3 months of age) at 1 month, 6 months or 10 months post switch. Male mice dietary switched from AL-DR in mid life adopted the metabolic phenotype of mice exposed to DR from early life, so by the 10-month timepoint the AL-DR mice overlapped significantly with the DR mice in terms of their metabolic phenotype. Those animals switched from DR-AL in mid life showed clear evidence of a glycemic memory, with significantly improved glucose tolerance relative to mice maintained exclusively on AL feeding from early life. This difference in glucose tolerance was still apparent 10 months after the dietary switch, despite body mass, fasting insulin levels and insulin sensitivity all being similar to AL mice at this time. Male C57BL/6 mice retain a long-term glycemic memory of early-life DR, in that glucose tolerance is enhanced in mice switched from DR-AL in mid life, relative to AL mice, even 10 months following the dietary switch. These data therefore indicate that the phenotypic benefits of DR are not completely dissipated following a return to AL feeding. The challenge now is to understand the molecular mechanisms underlying these effects, the time course of these effects and whether similar interventions can confer comparable benefits in humans.


The approach used to establish the safety of veterinary vaccines produced in the BHK 21 cell line.
A unique feature of the BHK 21 system is that the hamster provides a readily available and extremely sensitive (5, 13) assay system for process validation assays (Table IV outlines a production control scheme) since only between 5 and 100 cells are needed for tumors to form. While it was argued on theoretical grounds that a transforming agent active in a target species would not necessarily induce transformation in hamsters, clinical evidence has shown that the tumorigenicity of BHK 21 cells is a whole cell phenomenon. The main points to be drawn from the work with BHK 21/13 cells are as follows: 1. Cell culture technology now allows standardized, safe, effective, economical, large-scale vaccine production. 2. Although intact BHK 21 cells have been shown to be tumorigenic in hamsters, which is the species of origin for the cell line, no tumorigenic activity has been demonstrated in a variety of other aspects. 3. Even in hamsters, BHK 21 cells must be intact to cause tumor growth, a condition which can easily be avoided in biologicals production. 4. Decisions on the acceptability of a cell like the BHK 21 line were made on the basis of multiple species studies and validation of the manufacturing process to show that the final product was free of biologically active contaminants.


Classifying geometric variability by dominant eigenmodes of deformation in regressing tumours during active breath-hold lung cancer radiotherapy.
The purpose of this study is to develop and evaluate a lung tumour interfraction geometric variability classification scheme as a means to guide adaptive radiotherapy and improve measurement of treatment response. Principal component analysis (PCA) was used to generate statistical shape models of the gross tumour volume (GTV) for 12 patients with weekly breath hold CT scans. Each eigenmode of the PCA model was classified as 'trending' or 'non-trending' depending on whether its contribution to the overall GTV variability included a time trend over the treatment course. Trending eigenmodes were used to reconstruct the original semi-automatically delineated GTVs into a reduced model containing only time trends. Reduced models were compared to the original GTVs by analyzing the reconstruction error in the GTV and position. Both retrospective (all weekly images) and prospective (only the first four weekly images) were evaluated. The average volume difference from the original GTV was 4.3% ± 2.4% for the trending model. The positional variability of the GTV over the treatment course, as measured by the standard deviation of the GTV centroid, was 1.9 ± 1.4 mm for the original GTVs, which was reduced to 1.2 ± 0.6 mm for the trending-only model. In 3/13 cases, the dominant eigenmode changed class between the prospective and retrospective models. The trending-only model preserved GTV and shape relative to the original GTVs, while reducing spurious positional variability. The classification scheme appears feasible for separating types of geometric variability by time trend.


Correlation of histone methyl marks with circulating nucleosomes in blood plasma of cancer patients.
Circulating DNA is present in plasma/serum, mainly complexed with histones as nucleosomes. The detection of circulating nucleosomes (cNUCs) in the peripheral blood may be a diagnostic modality for cancer-associated changes of modified histone tails in blood circulation. In the present study, we investigated the correlation between the trimethylation of H3 lysine 9 (H3K9me3) and H4 lysine 20 (H4K20me3), which are hallmarks of pericentric heterochromatin, and cNUCs in healthy subjects and patients with colorectal cancer (CRC) and multiple myeloma (MM). The plasma concentration of cNUCs was measured using the Cell-Death Detection ELISA kit. Histone methylation marks were detected using chromatin immunoprecipitation (ChIP), followed by quantitative PCR with pericentric satellite 2 as the target sequence. The results showed a high variation in the concentrations of cNUCs, with healthy subjects exhibiting the lowest levels (median 0.194), the CRC patients intermediate (median 0.25) and the MM patients the highest levels (median 0.648). However, the differences between the groups did not reach statistical significance (p>0.05). Analysis using the Pearson's correlation test revealed a significant positive correlation between the concentration of cNUCs and H3K9me3 and H4K20me3 in the whole study group (N=57, p<0.001 for both histone marks). A study of the correlation between cNUCs and histone marks in the individual study groups demonstrated the correlation between cNUCs and H3K9me3 in CRC patients to be weak (p=0.046), indicating that circulating H3K9me3 may be modified in CRC patients. The histone marks were normalized using the values of cNUCs. In agreement with the weak correlation between cNUCs and H3K9me3 in CRC patients, H3K9me3 levels (median 0.047) were lowest in this group compared with the other two groups (0.06 in healthy subjects, 0.2 in MM patients, p = not significant). For H4K20me3, the median values were 0.022 in healthy subjects, 0.052 in CRC patients and 0.056 in MM patients. In conclusion, our findings indicate a marked correlation between cNUCs and histone methyl marks.


Cytotoxic effects of Phenformin on ovarian cancer cells: expression of HIF-1α and PDK1 in the hypoxic microenvironment.
Today, many anticancer drugs are used clinically for ovarian cancer, one of the leading causes of cancer-related deaths in women. Phenformin is an antidiabetic drug of the biguanide class. It improves the antiproliferative activity in cancer cells. Hypoxia is an important component associated with ovarian cancer and its tumor microenvironment. The aim of this study was to investigate the anticancer effects of Phenformin in SKOV-3 human ovarian cancer cells under hypoxic conditions. SKOV-3 human ovarian cancer cells treated with different doses of Phenformin (0.5 mM, 1 mM, 2 mM, 5 mM) for 24 hours were subjected to WST-1 cell viability assay and Annexin V apoptosis assay. A dose-dependent decrease in cell viability with Phenformin treatment was observed. In addition, Phenformin activated percentage of apoptotic SKOV-3 cancer cells in a dose-dependent manner. In this study, Cobalt(II) chloride (CoCl2) treatment leads to increased hypoxia-inducible factor-1alpha (HIF-1α) expression and Phenformin can recover hypoxic condition. HIF-1α protein expression was significantly correlated with cell viability assay and apoptosis assay. We also found that Phenformin inhibits expression of phosphoinositide-dependent kinase 1 (PDK1) in SKOV-3 ovarian cancer cells. The ability to migrate to cancer cells was significantly reduced in a dose-dependent manner with Phenformin. This data demonstrates that Phenformin treatment can induce apoptosis and inhibit proliferation in ovarian cancer cells under hypoxic conditions. The findings reveal that HIF-1α is a new target for the treatment of ovarian cancer.


Do new caledonian crows solve physical problems through causal reasoning?
The extent to which animals other than humans can reason about physical problems is contentious. The benchmark test for this ability has been the trap-tube task. We presented New Caledonian crows with a series of two-trap versions of this problem. Three out of six crows solved the initial trap-tube. These crows continued to avoid the trap when the arbitrary features that had previously been associated with successful performances were removed. However, they did not avoid the trap when a hole and a functional trap were in the tube. In contrast to a recent primate study, the three crows then solved a causally equivalent but visually distinct problem--the trap-table task. The performance of the three crows across the four transfers made explanations based on chance, associative learning, visual and tactile generalization, and previous dispositions unlikely. Our findings suggest that New Caledonian crows can solve complex physical problems by reasoning both causally and analogically about causal relations. Causal and analogical reasoning may form the basis of the New Caledonian crow's exceptional tool skills.


Serum transaminase levels in boys with Duchenne and Becker muscular dystrophy.
Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels are commonly used as biochemical indicators of hepatocellular injury but can also detect occult muscle disease. High concomitant serum creatine phosphokinase (CPK) levels can point to muscle as the source of high transaminase levels. Nevertheless, clinicians may be reluctant to attribute high transaminase levels to muscle. Study patients were boys with a genetic or biopsy-confirmed dystrophinopathy whose concomitant serum CPK, ALT, and AST levels were measured. We report 82 enzyme data sets from 46 patients with Duchenne muscular dystrophy (DMD) and 9 with Becker muscular dystrophy. Our results show a linear relationship between serum CPK and serum ALT and AST and a logarithmic relationship between serum enzyme levels and age for boys with DMD. We developed a mathematical model to predict serum ALT and AST levels when the serum CPK level and age are known. For 6 boys, initial failure to consider muscle as a cause of high transaminase levels led to delay of diagnosis and extensive testing for hepatic dysfunction. A second group of 4 boys with known DMD were investigated for liver disease after high transaminase levels were detected. Serum transaminase levels were highest in ambulant boys with DMD, whose levels reached 1220 U/L (ALT) (22.6 times higher than upper-limit normal levels) and 801 U/L (AST) (12.3 times higher than upper-limit normal levels). By recognizing muscle as a potential source of serum transaminase levels, clinicians can avoid unnecessary and invasive procedures, expedite clinical diagnosis, and avoid unnecessary cessation of concomitant drug therapy.


Using Serious Games to Increase Prevention and Self-Management of Chemotherapy-Induced Nausea and Vomiting in Older Adults With Cancer.
To examine the frequency and types of preventive and self-management behaviors reported by participants, as well as report acceptability and usability data for the electronic Symptom Self-Management Training-Chemotherapy-Induced Nausea and Vomiting (CINV) serious game. 80 adults who were aged 60 years or older and newly diagnosed with cancer were recruited from a community cancer center. Participants were randomized to an intervention or control group. A symptom management checklist was used to record preventive and self-management behaviors used after each chemotherapy treatment at home. Acceptability and usability were assessed using a brief survey. The intervention group reported using more preventive behaviors, and the control group reported using more self-management behaviors. Antiemetics were the most common strategy used, followed by dietary strategies. Participants rated all aspects of the serious game highly for usability and acceptability. Oncology providers can help older adults plan for self-managing treatment-related side effects at home. Recording self-management behaviors may reinforce the importance of active prevention and management of CINV.


A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.
Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. NCT02187302 (NIH).


Docetaxel (Taxotere) in the treatment of non-small cell lung cancer (NSCLC)--is there a role for a new chemotherapy programme?
Phase II with single-agent docetaxel, in second-line NSCLC, demonstrated an overall response rate of 20%, with a median response duration of 7 months and a median survival time of 9 months. These results suggested that docetaxel had promising activity in patients with platinum-resistant or refractory NSCLC. Phase III studies in this patient population subsequently confirmed this activity; docetaxel prolonged survival when compared to either vinorelbine/ifosfamide or the best supportive care. The phase II studies with docetaxel in first-line NSCLC produced an overall response rate of 30% in evaluable patients, with a median response duration of 6 months and a median survival time of 9 months. A phase III randomized study demonstrated a significant improvement in survival and time to progression with docetaxel, compared to the best supportive care. Based on the activity observed with single-agent docetaxel, combination and multimodality studies with docetaxel have also been conducted. Docetaxel is an active agent in first- and second-line NSCLC. Ongoing studies in the front-line treatment of NSCLC will further define the role of docetaxel in the neo-adjuvant setting.


Gaultheria Ethnobotany and Bioactivity: Blueberry Relatives with Anti-inflammatory, Antioxidant, and Anticancer Constituents.
Gaultheria, a genus belonging to the Ericaceae family, is typically a shrub that produces berries, and closely resembles the blueberry genus Vaccinium. Gaultheria species are used worldwide especially as food and medicine in China. Certain Gaultheria species are biologically active, as antioxidants, anti-inflammatories, and cytotoxic agents. Through literature searches and field surveys, the results of ethnobotanical uses, especially in China, as well as in vitro and in vivo studies are reviewed critically. This review examines the chemistry and bioactivity of this under-studied plant genus, and thus lays the groundwork for its future development for human health.


Thick Silicon Double-Sided Strip Detectors for Low-Energy Small-Animal SPECT.
This work presents characterization studies of thick silicon double-sided strip detectors for a high-resolution small-animal SPECT. The dimension of these detectors is 60.4 mm × 60.4 mm × 1 mm. There are 1024 strips on each side that give the coordinates of the photon interaction, with each strip processed by a separate ASIC channel. Our measurement shows that intrinsic spatial resolution equivalent to the 59 μm strip pitch is attainable. Good trigger uniformity can be achieved by proper setting of a 4-bit DAC in each ASIC channel to remove trigger threshold variations. This is particularly important for triggering at low energies. The thick silicon DSSD (Double-sided strip detector) shows high potential for small-animal SPECT.


Cdx mutant axial progenitor cells are rescued by grafting to a wild type environment.
Cdx transcription factors are required for axial extension. Cdx genes are expressed in the posterior growth zone, a region that supplies new cells for axial elongation. Cdx2(+/-)Cdx4(-/-) (Cdx2/4) mutant embryos show abnormalities in axis elongation from E8.5, culminating in axial truncation at E10.5. These data raised the possibility that the long-term axial progenitors of Cdx mutants are intrinsically impaired in their ability to contribute to posterior growth. We investigated whether we could identify cell-autonomous defects of the axial progenitor cells by grafting mutant cells into a wild type growth zone environment. We compared the contribution of GFP labeled mutant and wild type progenitors grafted to unlabeled wild type recipients subsequently cultured over the period during which Cdx2/4 defects emerge. Descendants of grafted cells were scored for their contribution to differentiated tissues in the elongating axis and to the posterior growth zone. No difference between the contribution of descendants from wild type and mutant grafted progenitors was detected, indicating that rescue of the Cdx mutant progenitors by the wild type recipient growth zone is provided non-cell autonomously. Recently, we showed that premature axial termination of Cdx mutants can be partly rescued by stimulating canonical Wnt signaling in the posterior growth zone. Taken together with the data shown here, this suggests that Cdx genes function to maintain a signaling-dependent niche for the posterior axial progenitors.


The transcriptomic fingerprint of glucoamylase over-expression in Aspergillus niger.
Filamentous fungi such as Aspergillus niger are well known for their exceptionally high capacity for secretion of proteins, organic acids, and secondary metabolites and they are therefore used in biotechnology as versatile microbial production platforms. However, system-wide insights into their metabolic and secretory capacities are sparse and rational strain improvement approaches are therefore limited. In order to gain a genome-wide view on the transcriptional regulation of the protein secretory pathway of A. niger, we investigated the transcriptome of A. niger when it was forced to overexpression the glaA gene (encoding glucoamylase, GlaA) and secrete GlaA to high level. An A. niger wild-type strain and a GlaA over-expressing strain, containing multiple copies of the glaA gene, were cultivated under maltose-limited chemostat conditions (specific growth rate 0.1 h-1). Elevated glaA mRNA and extracellular GlaA levels in the over-expressing strain were accompanied by elevated transcript levels from 772 genes and lowered transcript levels from 815 genes when compared to the wild-type strain. Using GO term enrichment analysis, four higher-order categories were identified in the up-regulated gene set: i) endoplasmic reticulum (ER) membrane translocation, ii) protein glycosylation, iii) vesicle transport, and iv) ion homeostasis. Among these, about 130 genes had predicted functions for the passage of proteins through the ER and those genes included target genes of the HacA transcription factor that mediates the unfolded protein response (UPR), e.g. bipA, clxA, prpA, tigA and pdiA. In order to identify those genes that are important for high-level secretion of proteins by A. niger, we compared the transcriptome of the GlaA overexpression strain of A. niger with six other relevant transcriptomes of A. niger. Overall, 40 genes were found to have either elevated (from 36 genes) or lowered (from 4 genes) transcript levels under all conditions that were examined, thus defining the core set of genes important for ensuring high protein traffic through the secretory pathway. We have defined the A. niger genes that respond to elevated secretion of GlaA and, furthermore, we have defined a core set of genes that appear to be involved more generally in the intensified traffic of proteins through the secretory pathway of A. niger. The consistent up-regulation of a gene encoding the acetyl-coenzyme A transporter suggests a possible role for transient acetylation to ensure correct folding of secreted proteins.


[Are the assessments of individual out-of-pocket health services of the IGeL-Monitor in line with clinical guidelines?]
The IGeL-Monitor of the Federal Medical Advisory Service in Germany evaluates the benefits and harms of individual out-of-pocket health services (in German: Individuelle Gesundheitsleistungen / IGeL). The aim of the analysis was to systematically compare IGeL-assessements with the recommendations from evidence-based guidelines. To identify guidelines, we conducted searches in guidelines databases (AWMF, Guidelines International Network and Trip database) and the websites of guideline organisations (February/March 2022). We included guidelines that were not older than 5 years. The methodological quality of the guidelines was assessed using the AGREE II instrument. We compared the recommendations with the IGeL-assessments in terms of content and grade of recommendation. We identified 41 guidelines covering 24 IGeL-assessements. 19 (79%) assessments (nearly) were in agreement with the guideline recommendations. No comparison was possible for 5 IGeL-assessements, because, for example, the recommendations were more specific. Ten of the 13 IGeL that were rated (tendentially) negatively were also not recommended in the guidelines. Overall, the IGeL-assessments were consistent with the recommendations of current guidelines. Accordingly, guideline groups seem to assess the evidence similarly to the IGeL-Monitor team. Insured persons should be informed honestly about the evidence, particularly for the (tendentially) negatively evaluated IGeL that are not recommended even in guidelines.


Infantile digital fibroma/fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up.
The clinicopathologic and immunohistochemical features of 69 pediatric examples of infantile digital fibroma/fibromatosis (IDF) were analyzed. Thirty males, 26 females, and 1 child (sex unstated) ranging from newborn to 120 months of age (median, 12 mo) manifested 74 lesions (5 identified in follow-up) involving the toe or finger (n=71) and the hand or foot (n=3). Tumors ranged in size from 3 to 35 (median, 10) mm. All but 4 study members presented with a solitary lesion. Metachronous IDFs developed in 7 patients within 17 to 82 months. Microscopically, a cytologically bland, fibroproliferative lesion was observed forming a dome-shaped/polypoid nodule directly beneath the epidermis and invading dermal adnexa. Mitotic figures per 20 high-powered fields ranged from 0 to 7 (median, 1). Paranuclear cytoplasmic inclusions were identified in 57 tumors. Tumor cells immunohistochemically expressed calponin (11 of 11 tumors), desmin (9/9), alpha-smooth muscle actin (11/11), CD99 (11/11), CD117 (6/8), heavy caldesmon (2/11 and scattered cytoplasmic inclusions in 4 tumors), CD10 (1/9), nuclear beta-catenin (2/11), and CD34 (1/11), but not muscle actin (HUC1-1), keratins, estrogen/progesterone receptor proteins, or activated caspase-3. Twenty-eight of 38 patients (74%) experienced recurrent/persistent disease (single in 22; multiple in 6) (median, 4 mo after surgery). One recurrent tumor spontaneously regressed and the size of another remained unchanged for almost 17 years before reexcision. All 23 patients with >5 years follow-up are currently disease free (median disease-free interval, 23 y). Minor postoperative functional/cosmetic complaints were reported in 47%. No patient with adequate clinical data developed the digitocutaneous dysplasia syndrome or a conventional fibromatosis, or relayed a family history of IDF/conventional fibromatosis. Our results indicate that IDF is a unique myofibroblastic process separable from conventional fibromatoses and from histologic mimics. Conservative excision or observation after biopsy (with additional surgery employed as necessary) are recommended treatment options.


Quantifying the effect of viewpoint changes on sensitivity to face identity.
Although faces can be recognized from different viewpoints, variations in viewpoint impair face identification ability. The present study quantified the effect of changes in viewpoint on sensitivity to face identity. We measured discrimination thresholds for synthetic faces presented from several viewpoints (same viewpoint condition) and the same faces shown with a change in viewpoint (5°, 10° or 20°) between viewing and test. We investigated three types of viewpoint change: (i) front-to-side (front-view matched to 20°° side-view), (ii) side-to-front (20° side-view matched to front) and (iii) symmetrical (10° left to 10° right). In the same viewpoint condition, discrimination thresholds were lowest for faces presented from 0° and increased linearly as the viewing angle was increased (threshold elevations: 0° = 1.00×, 5° = 1.11×, 10° = 1.22×, 20° = 1.69×). Changes in viewpoint between viewing and test led to further reductions in discrimination sensitivity, which depended upon the magnitude of viewpoint change (5° = 1.38×, 10° = 1.75×, 20° = 2.07×). Sensitivity also depended upon the type of viewpoint change: while a 20° front-to-side viewpoint change increased discrimination thresholds by a factor of 2.09×, a symmetrical change in viewpoint, of the same magnitude, did not significantly reduce sensitivity (1.26×). Sensitivity to face identity is significantly reduced by changes in viewpoint. Factors which determine the extent of this reduction include the magnitude of viewpoint change and symmetry. Our results support the premise of viewpoint-dependent encoding of unfamiliar face identities, and suggest that symmetry may be used to recognize identities across different viewpoints.


Geological Aspects of High-Pressure Research: High-pressure experimentation is providing a new look at problems in geophysics and petrology.
The low-density minerals that make up the bulk of rocks in the earth's crust, such as quartz and the feldspars, are transformed by high pressure into much denser phases. In some cases the products of these transitions are new phases that were first discovered in the laboratory; in other cases they are minerals such as kyanite, jadeite, and pyrope, which have long been known as constituents of metamorphic rocks. Determinations of the stability fields of these high-pressure minerals show that either metamorphism of sedimentary rocks takes place at much greater depth than has hitherto been supposed or pressures generated by orogenic forces may have significantly augmented the hydrostatic pressure. The second alternative seems unlikely, but lack of information on the strength of rocks during metamorphism makes the matter uncertain. Geophysical and petrological observations indicate that the dominant rock type in the upper mantle is garnet peridotite. However, there is reason to believe that the mantle is inhomogeneous and that a variety of rocks ranging in bulk composition from eclogite to peridotite are present. Hydrous phases, such as amphiboles, are possible constituents in the upper 100 kilometers. The hypothesis that the Mohorovicić discontinuity is a dynamic equilibrium between basalt and eclogite seems improbable. The transition zone between the upper and lower mantle can be explained as a series of reactions in which silicates with the silicon ion in fourfold coordination are transformed into phases in which silicon is in six-fold coordination. This interpretation is supported by synthesis of stishovite, a polymorph of SiO(2) with rutile structure, and by syntheses of germanate pyroxenes with ilmenite structure. Data on the melting of silicates at pressures up to 50 kilobars show that the initial dT/dP slopes of silicate melting curves are much steeper than those of metals but that they show considerable curvature. The increase of melting temperature with pressure should be much more pronounced near the top of the mantle than at greater depth.


Robust model-based vasculature detection in noisy biomedical images.
This paper presents a set of algorithms for robust detection of vasculature in noisy retinal video images. Three methods are studied for effective handling of outliers. The first method is based on Huber's censored likelihood ratio test. The second is based on the use of a alpha-trimmed test statistic. The third is based on robust model selection algorithms. All of these algorithms rely on a mathematical model for the vasculature that accounts for the expected variations in intensity/texture profile, width, orientation, scale, and imaging noise. These unknown parameters are estimated implicitly within a robust detection and estimation framework. The proposed algorithms are also useful as nonlinear vessel enhancement filters. The proposed algorithms were evaluated over carefully constructed phantom images, where the ground truth is known a priori, as well as clinically recorded images for which the ground truth was manually compiled. A comparative evaluation of the proposed approaches is presented. Collectively, these methods outperformed prior approaches based on Chaudhuri et al. (1989) matched filtering, as well as the verification methods used by prior exploratory tracing algorithms, such as the work of Can et aL (1999). The Huber censored likelihood test yielded the best overall improvement, with a 145.7% improvement over the exploratory tracing algorithm, and a 43.7% improvement in detection rates over the matched filter.


Effects of autologous platelet-rich plasma on cell viability and collagen synthesis in injured human anterior cruciate ligament.
Platelet-rich plasma is a fraction of plasma in which platelets are concentrated. It is reported to represent a source of multiple growth factors that promote tissue repair. In anticipation of the eventual testing of platelet-rich plasma in anterior cruciate ligament (ACL)-deficient patients, we examined the effect of autologous platelet-rich plasma on human ACL cell function in vitro. Fresh blood and ACL remnants were obtained from four patients who underwent ACL reconstruction surgery. Platelet-poor plasma and platelet-rich plasma were prepared from the blood samples. The concentrations of various growth factors in each preparation were tested with use of enzyme-linked immunosorbent assays. Isolated ACL cells were cultured in the presence of 5% fetal bovine serum, 5% platelet-poor clot releasate, 5% platelet-rich clot releasate, or 10% platelet-rich clot releasate. Platelet-rich plasma and platelet-poor plasma releasates were applied to the ACL cells from the same patient autologously. Cell viability and collagen synthesis in each group were analyzed, and semiquantitative gene-expression assays for type-I and III collagen were also performed. The concentrations of the main growth factors (transforming growth factor-beta, platelet-derived growth factor, epidermal growth factor, and vascular endothelial growth factor) were much higher in platelet-rich clot releasate than in platelet-poor clot releasate. In vitro treatment of ACL cells with platelet-rich clot releasate resulted in a significant increase in cell number compared with platelet-poor clot releasate. Total collagen production by the platelet-rich clot releasate-treated cells was significantly higher than that of the platelet-poor clot releasate-treated cells only because of enhanced cell proliferation. There was no significant effect of platelet-rich clot releasate treatment on gene expression for type-I collagen, but expression of type-III collagen was significantly enhanced by the treatment with platelet-rich clot releasate. These results suggest that autologous platelet-rich plasma can enhance ACL cell viability and function in vitro.


Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.
We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.


Inorganic photovoltaic cells based on BiFeO3: spontaneous polarization, lattice matching, light polarization and their relationship with photovoltaic performance.
Inorganic ferroelectric perovskite oxides are more stable than hybrid perovskites. However, their solar energy harvesting efficiency is not so good. Here, by constructing a series of BiFeO3-based devices (solar cells), we investigated three factors that influence the photovoltaic performance, namely, spontaneous polarization, terminated ion species in the interface between BiFeO3 and the electrode, and polarized light irradiation. This work was carried out under the framework of the density functional theory combined with the non-equilibrium Green's function theory under a built-in electric field or finite bias. The results showed that (1) the photocurrent is larger only under a suitable electronic band gap rather than larger spontaneous polarization; (2) the photocurrent reaches the largest value in the Bi3+ ion-terminated interface than in the case of Fe3+ or O2- with the SrTiO3 electrode; (3) the photocurrent can be largely enhanced if the polarized direction of the monochromatic light is perpendicular to the spontaneous polarization direction. These results would deepen the understanding of some experimental results of BiFeO3-based solar cells.


Pyridoxamine: the many virtues of a maillard reaction inhibitor.
Pyridoxamine (PM) is one of three natural forms of vitamin B6. It is a critical transient intermediate in catalysis of transamination reactions by vitamin B6-dependent enzymes. The discovery eight years ago that PM can inhibit the Maillard reaction stimulated new interest in this B6 vitamer as a prospective pharmacological agent for treatment of complications of diabetes. PM application in diabetic nephropathy has now progressed to a phase III clinical trial. Investigation of the PM mechanism of action demonstrated that PM inhibits post-Amadori steps of the Maillard reaction by sequestering catalytic metal ions and blocking oxidative degradation of Amadori intermediate. PM also has the capacity to scavenge toxic carbonyl products of sugar and lipid degradation, and to inhibit reactive oxygen species. These multiple activities position PM as a promising drug candidate for treatment of multifactorial chronic conditions in which oxidative reactions and/or carbonyl compounds confer pathogenicity.


Comparison of laser Doppler imaging, fingertip lacticemy test, and nailfold capillaroscopy for assessment of digital microcirculation in systemic sclerosis.
Laser Doppler imaging (LDI) is a relatively new method for assessing the functional aspect of superficial skin blood flow in systemic sclerosis (SSc) and Raynaud's phenomenon. The present study investigated the dynamic behavior of digital skin microvascular blood flow before and after cold stimulus (CS) in SSc patients and in healthy controls by means of a comprehensive approach of the functional (LDI), morphological (nailfold capillaroscopy (NFC)), and biochemical (fingertip lacticemy (FTL)) microcirculation components. Forty-four SSc patients and 40 healthy controls were included. After acclimatization, all subjects underwent NFC followed by LDI and FTL measurement. NFC was performed with a stereomicroscope under 10× to 20× magnification in the 10 digits of the hands. Skin blood flow of the dorsum of four fingertips (excluding the thumb) of the left hand was measured using LDI at baseline and for 30 minutes after CS. The mean finger blood flow (FBF) of the four fingertips was expressed as arbitrary perfusion units. FTL was determined on the fourth left finger before (pre-CS-FTL) and 10 minutes after CS. LDI showed significantly lower mean baseline FBF in SSc patients as compared with controls (296.9 ± 208.8 vs. 503.6 ± 146.4 perfusion units; P < 0.001) and also at all time points after CS (P < 0.001). There was a significant decrease in mean FBF after CS as compared with baseline in SSc patients and in controls, followed by recovery of the blood flow 27 minutes after CS in healthy controls, but not in SSc patients. FBF tended to be lower in patients with digital scars and previous ulceration/amputation (P = 0.06). There was no correlation between mean baseline FBF and NFC parameters. Interestingly, there was a negative correlation between FTL and FBF measured by LDI in basal conditions and 10 minutes after CS in SSc patients. LDI showed lower digital blood flow in SSc patients when compared with healthy controls and correlated well with FTL both at baseline and after CS, allowing objective measurement of blood perfusion in SSc patients. The lack of correlation between functional and morphological microvascular abnormalities, measured by LDI and NFC, suggests they are complementary tools for evaluation of independent microangiopathy aspects in SSc patients.


Fulvestrant and the sequential endocrine cascade for advanced breast cancer.
Following relapse on endocrine therapy for advanced, hormone receptor-positive breast cancer, it is common for patients to experience responses to alternative endocrine agents. Fulvestrant ('Faslodex') is a new type of endocrine treatment--an oestrogen receptor (ER) antagonist with no agonist effects. Fulvestrant downregulates cellular levels of the ER resulting in decreased expression of the progesterone receptor. This unique mode of action means that it is important that fulvestrant is placed optimally within the sequence of endocrine therapies to ensure that patients gain maximum benefit. Fulvestrant has shown efficacy when used after progression on tamoxifen or anastrozole in postmenopausal women with advanced breast cancer. After progression on fulvestrant, subsequent endocrine treatments can produce responses in many patients, demonstrating that fulvestrant does not lead to crossresistance with other endocrine therapies. Responses to fulvestrant have also been observed in patients heavily pretreated with prior endocrine therapy. Fulvestrant is a versatile endocrine agent that may be integrated into the therapeutic sequence prior to, or subsequent to, other hormonal therapies, and represents a valuable additional antioestrogen for the treatment of postmenopausal women with advanced breast cancer.


Nursing's contribution to general practice: general practitioners' and practice nurses' views.
This study was instigated by the paucity of knowledge relating to the work of nurses employed by general practitioners in Australia and the phenomenal development of the practice nurse role in the United Kingdom. A mailed survey of general practitioners and practice nurses within one Division of General Practice in South-East Queensland, sought, among other things, their views about the current and potential contribution of nursing to general practice. Eighty-four out of 164 (51%) general practitioners and 37 out of 67 (55%) practice nurses responded to the survey. Results indicated that both general practitioners and practice nurses appreciated the value of nursing services in general practice and would sanction the employment of more nurses especially for the purpose of preventive care. The majority of nurses were agreeable to the notion that the nurse's role could, and should, be expanded to include autonomous functioning while most of the doctors were amenable to some extension of nursing practice but reticent or opposed to any independent interventions.


Animal models of diabetes mellitus for islet transplantation.
Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study.


Identifying maltreatment subgroups with patterns of maltreatment subtype and chronicity: A latent class analysis approach.
Maltreatment experiences are complex, and it is difficult to characterize the heterogeneity in types of maltreatment. Subtypes, such as emotional maltreatment, sexual abuse, physical abuse, and neglect commonly co-occur and may persist across development. Therefore, treating individual maltreatment subtypes as independently occurring is not representative of the nature of maltreatment as it occurs in children's lives. Latent class analysis (LCA) is employed herein to identify subgroups of maltreated children based on commonalities in maltreatment subtype and chronicity. In a sample of 674 low-income urban children, 51.6% of whom experienced officially documented maltreatment, our analyses identified four classes of children, with three distinct classes based on maltreatment subtypes and chronicity, and one group of children who did not experience maltreatment. The largest class of maltreated children identified was the chronic, multi-subtype maltreatment class (57% of maltreated children); a second class was characterized by only neglect in a single developmental period (31% of maltreated children), and the smallest class was characterized by a single subtype of maltreatment (emotional maltreatment, physical, or sexual abuse) occurring in a single developmental period (12% of maltreated children). Characterization of these groups confirms the overlapping nature of maltreatment subtypes. There were notable differences between latent classes on child behavioral and socio-emotional outcomes measured by child self-report and camp counselors report during a one-week summer camp. The largest differences were between the non-maltreated class and the chronic maltreatment class. Children who experienced chronic, multi-subtype maltreatment showed higher levels of externalizing behavior, emotion dysregulation, depression, and anxiety.


DNA-Assembled Multilayer Sliding Nanosystems.
DNA nanotechnology allows for the realization of complex nanoarchitectures in which the spatial arrangements of different constituents and most functions can be enabled by DNA. When optically active components are integrated in such systems, the resulting nanoarchitectures not only provide great insights into the self-assembly of nanoscale elements in a systematic way but also impart tailored optical functionality to DNA origami. In this Letter, we demonstrate DNA-assembled multilayer nanosystems, which can carry out coordinated and reversible sliding motion powered by DNA fuels. Gold nanoparticles cross-link DNA origami filaments to define the configurations of the multilayer nanoarchitectures as well as to mediate relative sliding between the neighboring origami filaments. Meanwhile, the gold nanoparticles serve as optical probes to dynamically interact with the fluorophores tethered on the filaments, rendering in situ detection of the stepwise sliding processes possible. This work seeds the basis to implement DNA-assembled complex optical nanoarchitectures with programmability and addressability, advancing the field with new momentum.


The efficacy of erythropoietin on acute spinal cord injury. An experimental study on a rat model.
The accumulated knowledge of erythropoietin (EPO) interaction in neural injury has led to potentially novel therapeutic strategies. Previous experimental studies of recombinant human EPO (rhEPO) administration have shown favorable results after central and peripheral neural injury. In the present study we used the aneurysmal clip model to evaluate the efficacy of two different regimes of rhEPO administration on the functional outcome after severe acute spinal cord injury (ASCI). Thirty rats were operated on with posterior laminectomy at thoracic 10th vertebra. Spinal cord trauma produced by extradural placement of the aneurysm clip, for 1 min. Animals were divided into three groups; the first group received a low total EPO dose (EPO-L), (2 doses of 1,000 IU each s.c.). The second group was administered the high total EPO dose (EPO-H), (14 doses of 1,000 IU each s.c.), and the third was the Control group, which received normal saline in the same time fashion with EPO-H group. Follow-up was for 6 weeks. Estimation of the functional progress of each rat was calculated using the locomotor rating scale of Basso et al, with a range from 0 to 21. After surgery the animals suffered paraplegia with urinary disturbances. Rats that received EPO demonstrated statistically significant functional improvement compared to the Control group, throughout study interval. On the last follow-up at 6 weeks the EPO-L rats achieved a mean score 17.3 +/- 1.15, the EPO-H 14.7 +/- 1.82, and the control group 8.2 +/- 0.78. Comparison between the two EPO groups reveals superior final outcome of the group treated with lower total dose. Our study supports current knowledge, that EPO administration has a positive effect on functional recovery after experimental ASCI. These data reflect the positive impact of EPO on the pathophysiologic cascade of secondary neural damage. However, we observed a dose-related effect on functional recovery. Interestingly, large doses do not seem to favor the neurological recovery as lower doses do.


Antidiabetic Effect of a New Original NT-3 Dipeptide Mimetic.
It was previously established that the original dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), has a pronounced neuroprotective effect in vitro at concentrations of 10-5-10-12 М. In the present study, experiments on the streptozotocin-induced diabetes model in C57Bl/6 mice showed that GTS-301, when administered intraperitoneally for 32 days at doses of 0.1 and 0.5 mg/kg, has antidiabetic activity manifested in a reduction of hyperglycemia and polydipsia and in an increase in animal survival. The results obtained confirm the concept of the similarity of neurochemical mechanisms underlying the regulation of functions of neurons and β-cells.


[A giant malignant tumour of the skull-Case report and differential diagnosis].
The case of a 72-year-old woman with a high-partially located tumor grown within a half year to a magnitude of 8.5 x 11 x 11 cm is reported. The patient remembered a mastectomy and axillary lymphadenectomy followed by chemotherapy and radiation 8 years ago. Therefore we assumed a skeletal metastasis of a breast cancer. After wide excision, an unusual morphology was found, allowing only a classification as a pleomorphic sarcoma. Searching for the pathohistological evaluation of the former breast tumor, a cystosarcoma phylloides malignum could be found out. The tumor described here can be identified as a metastasis of this rare neoplasm.


Location and chemical synthesis of a binding site for HIV-1 on the CD4 protein.
The human immunodeficiency virus type 1 (HIV-1) uses the CD4 protein as a receptor for infection of susceptible cells. A candidate structure for the HIV-1 binding site on the CD4 protein was identified by epitope mapping with a family of eight functionally distinct CD4-specific monoclonal antibodies in conjunction with a panel of large CD4-derived synthetic peptides. All of the seven epitopes that were located reside within two immunoglobulin-like disulfide loops situated between residues 1 and 168 of the CD4 protein. The CD4-specific monoclonal antibody OKT4A, a potent inhibitor of HIV-1 binding, recognized a site between residues 32 and 47 on the CD4 protein. By analogy to other members of the immunoglobulin superfamily of proteins, this particular region has been predicted to exist as a protruding loop. A synthetic analog of this loop (residues 25 to 58) showed a concentration-dependent inhibition of HIV-1-induced cell fusion. It is proposed that a loop extending from residues 37 to 53 of the CD4 protein is a binding site for the AIDS virus.


Analysis of the Efficacy and Safety of Increasing the Energy Dose Applied Per Session by Increasing the Number of Shock Waves in Extracorporeal Lithotripsy: A Prospective and Comparative Study.
To evaluate the efficacy and safety of increasing the energy dose in treating urinary lithiasis with extracorporeal lithotripsy through an expanded number of Shock Waves Per Session (SWPS). a randomized, prospective, and comparative study was performed with patients with renal or ureteral lithiasis from 2011 to 2014. Two groups were studied: Group A (n = 136), treated with 3500 SWPS, and Group B (n = 171), subjected to an expanded treatment with 7000 SWPS. Patients were considered stone free when there was no lithiasis or it were less or equal to 4 mm after treatment. Variables related to the patient, stones, treatment, and complications were collected. The global SFR was 75.0% and 87.7% in Groups A and B, respectively (p = 0.004). In renal location, the SFR was higher in Group B (74.1% vs 90.7%, p = 0.003) regardless of the size. In the ureteral location, there were differences in the pelvic only (73.7% vs 95.2%). There were no differences in either the complication rate (27.2% vs 25.7%, p = 0.77), or the severity between the two groups. The variable "number of SWPS" was seen to be an independent predictor of the resolution of lithiasis, having the probability of resolving lithiasis 2.62 (CI 95% = 1.40-4.89) times greater when applying 7000 SWPS. In our study, increasing the energy dose applied through an expanded number of SWPS has been shown to be more effective than standard regimens with a similar safety profile. However, more clinical studies on different types of lithotripters are required to confirm these results.


Comment on "Tail reconnection triggering substorm onset".
Angelopoulos et al. (Research Articles, 15 August 2008, p. 931) reported that magnetic reconnection in Earth's magnetotail triggered the onset of a magnetospheric substorm. We provide evidence that (i) near-Earth current disruption, occurring before the conventional tail reconnection signatures, triggered the onset; (ii) the observed auroral intensification and tail reconnection are not causally linked; and (iii) the onset they identified is a continuation of earlier substorm activities.


B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions.
Multiple sclerosis (MS) lesions in the CNS are characterized by disseminated demyelination with perivascular infiltrates of macrophages, T cells, and B cells. To investigate the origin and characteristics of the B cell population found in MS plaque tissue, we performed molecular studies in 10 MS patients and 4 non-MS control samples. Ig transcripts from the perivascular infiltrated brain lesions were analyzed by complementary-determining region 3 spectratyping to ascertain the B cell heavy chain gene rearrangement repertoire expressed in MS brains. Significant rearrangement diversity and deviation from the normal Ig heavy (H) chain repertoire was observed. The cloning and sequencing of RT-PCR products from families VH1 and VH4 showed a correlation with the profiles obtained by spectratyping. Generally, restricted spectratyping patterns concurred with repetition of in-frame complementary-determining region 3 identical sequences. The analysis of heavy chain variable (VH), diversity (D), and joining (JH) gene segments revealed the increased usage of VH1-69, VH4-34, and VH4-39. Similarly, gene segments from families D2, D3, and JH4 were over-represented. The presence of restricted patterns of rearranged Ig mRNA within the plaque lesion suggests that Ab production in the demyelinating plaque is a local phenomenon and supports the idea that in MS an Ag-driven immune response might be responsible for demyelination.


Time-updated systolic blood pressure and the progression of chronic kidney disease: a cohort study.
Previous reports of the longitudinal association between achieved blood pressure (BP) and end-stage renal disease (ESRD) among patients with chronic kidney disease (CKD) have not incorporated time-updated BP with appropriate covariate adjustment. To assess the association between baseline and time-updated systolic blood pressure (SBP) with CKD progression. Observational, prospective cohort study. (ClinicalTrials.gov: NCT00304148). 7 U.S. clinical centers. Patients in the Chronic Renal Insufficiency Cohort Study (n = 3708) followed for a median of 5.7 years (25th to 75th percentile, 4.6 to 6.7 years). The mean of 3 seated SBP measurements made up the visit-specific SBP. Time-updated SBP was the mean of that and all previous visits. Outcomes were ESRD and the composite end point of ESRD or halving of the estimated glomerular filtration rate. Analyses investigating baseline and time-updated SBP used Cox proportional hazards models and marginal structural models, respectively. Systolic blood pressure was 130 mm Hg or greater at all visits in 19.2% of patients. The hazard ratio for ESRD among patients with SBP of 130 to 139 mm Hg, compared with SBP less than 120 mm Hg, was 1.46 (95% CI, 1.13 to 1.88) using only baseline data and 2.37 (CI, 1.48 to 3.80) using time-updated data. Among patients with SBP of 140 mm Hg or greater, corresponding hazard ratios were 1.46 (CI, 1.18 to 1.88) and 3.37 (CI, 2.26 to 5.03) for models using only baseline data and those using time-updated data, respectively. Blood pressure was measured once annually, and the cohort was not a random sample. Time-updated SBP greater than 130 mm Hg was more strongly associated with CKD progression than analyses based on baseline SBP. National Institute of Diabetes and Digestive and Kidney Diseases.


Traveling waves in a model for cortical spreading depolarization with slow-fast dynamics.
Cortical spreading depression and spreading depolarization (CSD) are waves of neuronal depolarization that spread across the cortex, leading to a temporary saturation of brain activity. They are associated with various brain disorders such as migraine and ischemia. We consider a reduced version of a biophysical model of a neuron-astrocyte network for the initiation and propagation of CSD waves [Huguet et al., Biophys. J. 111(2), 452-462, 2016], consisting of reaction-diffusion equations. The reduced model considers only the dynamics of the neuronal and astrocytic membrane potentials and the extracellular potassium concentration, capturing the instigation process implicated in such waves. We present a computational and mathematical framework based on the parameterization method and singular perturbation theory to provide semi-analytical results on the existence of a wave solution and to compute it jointly with its velocity of propagation. The traveling wave solution can be seen as a heteroclinic connection of an associated system of ordinary differential equations with a slow-fast dynamics. The presence of distinct time scales within the system introduces numerical instabilities, which we successfully address through the identification of significant invariant manifolds and the implementation of the parameterization method. Our results provide a methodology that allows to identify efficiently and accurately the mechanisms responsible for the initiation of these waves and the wave propagation velocity.


Impaired nocturnal melatonin secretion in non-dipper hypertensive patients.
Melatonin plays a role in the biologic regulation of circadian rhythms, including sleep. Melatonin has also been shown to modulate vascular smooth muscle tone and to induce hemodynamic effects in humans. To evaluate whether melatonin plays a role in the circadian rhythm of blood pressure in hypertensive patients. Sixteen elderly patients with essential hypertension were evaluated. Patients were defined as either dippers (DIP, n = 8) or non-dippers (NDIP, n = 8) according to the nocturnal change in the mean arterial pressure (MAP). 6-Sulfatoxymelatonin (6-SMT), the main melatonin metabolite, was determined by enzyme-linked immunosorbent assay (ELISA) in two separate urine collections, one in the daytime and one during the night. Both groups of DIP and NDIP hypertensives were comparable in regard to age and sex. During the night, the mean arterial pressure decreased by 10.3 +/- 2.2% in the DIP and increased by 7.5 +/- 1.7% in the NDIP group (p < 0.01). Daily 6-SMT was comparable in DIP (3.28 +/- 0.87 microg/12 h) and NDIP (2.31 +/- 0.68 microg/12 h) (p = 0.39). However, while the DIP presented the physiological nocturnal increase in urinary 6-SMT (mean 8.19 +/- 1.68 microg/ 12 h), this surge of melatonin production was missing in NDIP in whom nocturnal urinary 6-SMT concentrations were not significantly different from daily levels (mean 2.56 +/- 0.79 microg/12 h). The nocturnal change in urinary 6-SMT excretion was positively correlated to the nocturnal change in MAP (R = 0.54; p = 0.031). NDIP hypertensive patients differ from DIP hypertensives by having an impaired nocturnal melatonin secretion. Thus, melatonin may play a role in the circadian rhythm of blood pressure in hypertensive patients.


Adenovirus-mediated overexpression of follistatin enlarges intact liver of adult rats.
Under normal physiologic conditions, liver size is under strict regulatory control. Activin, a member of the transforming growth factor beta (TGF-beta) superfamily, is expressed in the intact adult liver and is an inhibitor of hepatocyte growth. However, the exact role played by endogenous activin in maintaining the size of a normal adult liver has yet to be completely examined in vivo. Here, we report the development of an adenoviral vector (AdexCAFS288) that expressed human follistatin-288, which binds to activin and neutralizes its biologic activities. AdexCAGFP, a control virus, expressed green fluorescent protein. AdexCAFS288 effectively expressed follistatin-288, as measured both in HepG2 cell lysate and conditioned medium and blocked activin signaling and its biologic functions in vitro. Intraperitoneal injection of AdexCAFS288 in vivo resulted in significant liver growth (146% of control) in intact liver of adult male rats 12 days following treatment without significant dysfunctions. The increase in liver size was attributed to increased hepatocyte proliferation, as monitored by the mitotic index. Furthermore, there was a significant correlation between serum follistatin levels and liver weight. In conclusion, our results suggest that activin plays a critical role in maintaining optimal liver size and implicates the endogenous activin system as a therapeutic target in the treatment of liver disease.


Clinical cardiac electrophysiologic study of celiprolol.
The objective of the study was to evaluate the acute effect of intravenous celiprolol on the electrophysiologic properties of the cardiac conduction system in man and to assess potential problems in terms of its causing heart block or sinus bradycardia. Eight patients with controlled coronary artery disease and hypertension but without conduction system disease were studied. All cardiac drugs e.g., digoxin, sympathomimetics and other beta blockers were discontinued prior to entering the study. Surface ECG leads I, AVF, and Vi were applied to each patient, and the ECG was continuously displayed on an oscilloscope. A quadripolar stimulating electrode (7F) was inserted percutaneously and positioned in the high right atrium and a tripolar or bipolar His bundle recording catheter was positioned cross the tricuspid valve. The atrial and His bundle electrograms were recorded on a direct writing recorder. After completion of the baseline electrophysiologic (EP) measurements, in an open fashion, celiprolol (0.1 mg/kg) was administered intravenously at the rate of 1 mg/min into each of the five patients. The complete battery of the EP measurements were repeated immediately following completion of the infusion. Preliminary data in eight patients demonstrated no significant effect of celiprolol on the cardiac conduction system.


Differences between unipolar mania and bipolar-I disorder: Evidence from nine epidemiological studies.
Although clinical evidence suggests important differences between unipolar mania and bipolar-I disorder (BP-I), epidemiological data are limited. Combining data from nine population-based studies, we compared subjects with mania (M) or mania with mild depression (Md) to those with BP-I with both manic and depressive episodes with respect to demographic and clinical characteristics in order to highlight differences. Participants were compared for gender, age, age at onset of mania, psychiatric comorbidity, temperament, and family history of mental disorders. Generalized linear mixed models with adjustment for sex and age as well as for each study source were applied. Analyses were performed for the pooled adult and adolescent samples, separately. Within the included cohorts, 109 adults and 195 adolescents were diagnosed with M/Md and 323 adults and 182 adolescents with BP-I. In both adult and adolescent samples, there was a male preponderance in M/Md, whereas lifetime generalized anxiety and/panic disorders and suicide attempts were less common in M/Md than in BP-I. Furthermore, adults with mania revealed bulimia/binge eating and drug use disorders less frequently than those with BP-I. The significant differences found in gender and comorbidity between mania and BP-I suggest that unipolar mania, despite its low prevalence, should be established as a separate diagnosis both for clinical and research purposes. In clinical settings, the rarer occurrence of suicide attempts, anxiety, and drug use disorders among individuals with unipolar mania may facilitate successful treatment of the disorder and lead to a more favorable course than that of BP-I disorder.


Multicomponent assessment and treatment of cigarette pica.
We conducted a multicomponent assessment and treatment for 4 individuals who engaged in cigarette pica. During Phase 1, three stimulus preference assessments were conducted to identify (a) the reinforcing component of the cigarette, (b) potential alternative reinforcers that may be used during treatment, and (c) whether the alternative reinforcer would compete effectively with cigarettes. Results were successful in identifying the reinforcing component of the cigarette and suggested the feasibility of using alternative reinforcers during treatment to eliminate cigarette pica. During Phase 2, the effects of two treatment procedures were evaluated. Noncontingent reinforcement (NCR) with the alternative edible reinforcer reduced the pica of 2 of the participants, but effects were not maintained when the initial dense schedule of NCR was thinned. Subsequently, differential reinforcement of alternative behavior with the alternative edible reinforcer was effective in reducing pica for 3 participants. An evaluation of nine treatment procedures failed to identify an effective intervention for the remaining participant; consequently, preventive measures were designed to minimize occurrences of cigarette pica.


A genomic-based approach combining in vivo selection in mice to identify a novel virulence gene in Leishmania.
Infection with Leishmania results in a broad spectrum of pathologies where L. infantum and L. donovani cause fatal visceral leishmaniasis and L. major causes destructive cutaneous lesions. The identification and characterization of Leishmania virulence genes may define the genetic basis for these different pathologies. Comparison of the recently completed L. major and L. infantum genomes revealed a relatively small number of genes that are absent or present as pseudogenes in L. major and potentially encode proteins in L. infantum. To investigate the potential role of genetic differences between species in visceral infection, seven genes initially classified as absent in L. major but present in L. infantum were cloned from the closely related L. donovani genome and introduced into L. major. The transgenic L. major expressing the L. donovani genes were then introduced into BALB/c mice to select for parasites with increased virulence in the spleen to determine whether any of the L. donovani genes increased visceral infection levels. During the course of these experiments, one of the selected genes (LinJ32_V3.1040 (Li1040)) was reclassified as also present in the L. major genome. Interestingly, only the Li1040 gene significantly increased visceral infection in the L. major transfectants. The Li1040 gene encodes a protein containing a putative component of an endosomal protein sorting complex involved with protein transport. These observations demonstrate that the levels of expression and sequence variations in genes ubiquitously shared between Leishmania species have the potential to significantly influence virulence and tissue tropism.


Large structural changes upon protonation of Fe4S4 clusters: the consequences for reactivity.
Density functional calculations reveal that protonation of a μ3-S in [Fe4S4X4](2-) clusters (X = halide, thiolate, phenoxide) results in the breaking of one S-Fe bond (to >3 Å, from 2.3 Å). This creates a doubly-bridging SH ligand (μ3-SH is not stable), and a unique three-coordinated planar Fe atom. The under-coordination of this unique Fe atom is the basis of revised mechanisms for the acid-catalysed ligand substitution reactions in which substitution of X by PhS occurs at the unique Fe site by an indirect pathway involving initial displacement of X by acetonitrile (solvent), followed by displacement of coordinated acetonitrile by PhSH. When X = Cl or Br the rate of attack by PhSH is slower than the dissociation of X(-), and is the rate-determining step; in contrast, when X = SEt, SBu(t) or OPh the rate of dissociation of XH is slower than attack by PhSH and is rate-determining for these clusters. A full and consistent interpretation of all kinetic data is presented including new explanations of many of the kinetic observations on the acid-catalysed substitution reactions of [Fe4S4X4](2-) clusters. The proposed mechanisms are supported by density functional calculations of the structures of intermediates, and simulations of some of the steps. These findings are expected to have widespread ramifications for the reaction chemistry of both natural and synthetic clusters with the {Fe4S4} core.


Comparison of restriction endonuclease cleavage patterns in salmonid herpesvirus DNAs.
Herpesvirus salmonis (H. salmonis) and seven strains of Oncorhynchus masou virus (OMV) were analyzed for their genomes with restriction endonucleases HindIII and PstI. Restriction profiles of H. salmonis were different from those of OMV strains. Restriction patterns of OMV strain DNAs were divided into four subtypes with HindIII. With PstI digestion, DNA restriction patterns of those strains were divided into five subtypes. Obvious difference in restriction patterns was not observed among tumor tissue-derived and coelomic fluids-derived strains. By using 32P-labelled DNA of standard OMV (strain 00-7812) as a probe, H. salmonis DNA was not hybridized, but most of the fragments of OMV strain DNAs were hybridized.


Fulminant Guillain-Barré syndrome after closed head injury: a potentially reversible cause of an ominous examination. Case report.
Fulminant Guillain-Barré syndrome (GBS) is a rapidly progressive form of polyneuropathy in which patients demonstrate eventual flaccid quadriplegia and an absence of brainstem function. Most patients present after a mild upper respiratory or gastrointestinal illness and have nondiagnostic cerebral imaging studies. The authors present a case of fulminant GBS that developed in a 55-year-old alcoholic man 1 week after admission for a closed head injury. The details of this case and a discussion of GBS will be presented. This case provides evidence for combined central and peripheral nervous system involvement in severe cases of GBS. Recognition of fulminant GBS is important to prevent inappropriate declaration of brain death or withdrawal of support in the face of a potentially reversible process.


Diarrheal response of gnotobiotic pigs after fetal infection and neonatal challenge with homologous and heterologous human rotavirus strains.
Pigs exposed in utero to human rotavirus (HRV) strain Wa serotype 1 from 15 to 36 days prior to birth responded immunologically by modifying their clinical response to neonatal oral challenge with a pathogenic dose of homologous Wa or heterologous M serotype 3 HRV. In these cases, diarrhea was prevented in 12 of 14 pigs and greatly reduced in the other two. However, fecal virus shedding was not significantly modified, since it was detected in 12 of 14 pigs. These results suggest the existence of a closer antigenic relationship between these two different HRV serotypes which may only be expressed in an in vivo test system. Exposure of fetal pigs to HRV DS-1 serotype 2 failed to cause infection or to induce any protection when pigs were challenged at birth with HRV Wa. This model for cross-protection studies in gnotobiotic piglets offers good possibilities for the evaluation of potential HRV vaccine candidates, for the in vivo study of antigenic similarities between rotavirus serotypes, and for the understanding of protective immune responses against diarrhea and virus shedding.


Conformational properties of heterogeneous arabinoxylan protein gums from corn bran and distillers grains in comparison with gum arabic.
The molecular structure and conformation of arabinoxylan-protein gum, commonly referred as corn fiber gum (CFG) were analyzed by high-performance size-exclusion chromatography (HPSEC) coupled with RI, UV, light scattering and viscometer detectors. CFG had a heterogeneous structure. The detailed conformation of CFG at different molecular weights was compared with that of hemicellulose fiber gum (HFG) from dried distiller's grains with solubles and gum arabic. The CFG molecules mainly had random coil conformation; only 10 % of them exhibited rigid rod conformation. Approximately 80 % of the CFG had a molecular weight between 105 and 105.4 Da, while the other 20 % of molecules were between 105.4 and 1.5 × 107.7 Da. The overall conformational properties of CFG and HFG were closer but differed from that of gum arabic. The intrinsic viscosity and radius of gyration of both CFG and HFG were greater than those of gum arabic although the average molecular weight of CFG and HFG was lower. The protein and carbohydrate were covalently linked in CFG molecules as shown by the HPSEC-multiple detectors combined with partial acid hydrolysis. Based on the detailed conformation of CFG and the methylation analysis, 1D and 2D NMR spectroscopy results, the molecular structure of CFG was proposed.


Language Underperformance in Young Children Who Are Deaf or Hard-of-Hearing: Are the Expectations Too Low?
(1) To examine language performance in the context of cognitive abilities in young children who are deaf or hard-of-hearing and (2) to identify factors associated with having a language underperformance, defined as a gap between the language standard score and the nonverbal IQ (NVIQ) standard score. Children 6 to 82 months of age with bilateral hearing loss were enrolled. Language performance was defined as a ratio of language skills relative to cognitive abilities with language underperformance defined as a ratio of language scores to NVIQ <0.85. Among 149 children, approximately half had hearing loss that was clinically classified as mild or moderate, and over one-third received a cochlear implant. Participants had a mean NVIQ in the average range (95.4 [20.3]). Receptive language scores were significantly lower than their NVIQ by 10.6 points (p < .0001). Among children with NVIQs 80 to 100, 62.5% had receptive scores <85 and 50% had a language underperformance (ratio <0.85). Among children with NIVQs >100, 21.1% had receptive scores <85 with 42% having a language underperformance. Children with language underperformance (n = 61, 41.5%) were more likely to have more severe levels of hearing loss, lower socioeconomic status, and be nonwhite. Many children early identified with hearing loss continue to demonstrate language underperformance, defined using their cognitive potential. Language deficits have a cascading effect on social functioning in children who are deaf or hard-of-hearing. This study highlights the need to understand a child's cognitive potential to adequately address language needs in existing intervention models.


Complications of foot surgery. Nonunions and related disorders.
Management of malunions, delayed unions, and nonunions is a complex task that initially requires appropriate diagnosis and classification. Diagnostic modalities currently used include radiography, fluoroscopy, tomography, computed tomography, and radionucleotide evaluations. Based on these evaluations, nonunions may be classified as hypervascular or avascular in nature. Determining the presence of a synovial pseudoarthrosis or infection is also vital to nonunion management. Current treatment regimens available include combinations of cast immobilization, electrical stimulation, and surgical repair with and without bone graft. Internal and external fixation also provide rigid stability to promote healing of nonunion sites. Infected nonunions should be managed with appropriate surgical debridement and antibiotics. Internal fixation in the presence of infection may not necessarily need to be removed. There is no single best method for treatment of nonunions. Therapy must be tailored to each individual to provide a cure.


Online Resources for Rotator Cuff Repair: What are Patients Reading?
The purpose of this study was to use a novel scoring system to evaluate the content and grade the quality of websites that patients may use to learn about rotator cuff repair. Two search terms ("rotator cuff repair" and "rotator cuff surgery") were entered into 3 Internet search engines (Google, Yahoo, and Bing). We scored the quality of information using a novel scoring system. Website quality was further assessed by the Journal of the American Medical Association (JAMA) benchmark criteria and Health on the Net Foundation (HON) code certification. The readability of the websites was evaluated with the Flesch-Kincaid score. We evaluated 47 websites. The average quality for all websites was 6.47 ± 5.21 (maximum 20 points). There was a large difference in scores between the top 5 websites and the remaining websites (16.30 vs 5.51, P < .001). There was no difference in scores when comparing the 3 different search engines (P = .85). The mean reading level was 10.17 ± 2.24. Reading level was not significantly correlated with quality (rs = 0.14, P = .36). The average JAMA benchmark criteria score for all websites was 2.34 ± 1.11 (maximum 4 points). JAMA criteria score was not significantly correlated with quality (rs = 0.02, P = .91). Sites without HONcode certification had higher quality scores (8.33 ± 4.80) than sites with HONcode certification (6.18 ± 4.66), but this difference was not statistically significant (P = .15). The quality of patient-level information on rotator cuff repair on the Internet is both incomplete and written at a reading level higher than current recommendations. Information quality is not significantly correlated with reading level or JAMA criteria, and does not depend on the search term used or HONcode certification. Patients having rotator cuff repair may seek information on the Internet; the information may require surgeon clarification.


Pharmacokinetic/Pharmacodynamic Target Attainment of Tigecycline in Patients with Hepatic Impairment in a Real-World Setting.
This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of various tigecycline dosing regimens in real-world patients with impaired liver function. The clinical data and serum concentrations of tigecycline were extracted from the patients' electronic medical records. Patients were classified into Child-Pugh A, Child-Pugh B, and Child-Pugh C groups, according to the severity of liver impairment. Furthermore, the minimum inhibition concentration (MIC) distribution and PK/PD targets of tigecycline from the literature were used to obtain a proportion of PK/PD targets attainment of various tigecycline dosing regimens at different infected sites. The pharmacokinetic parameters revealed significantly higher values in moderate and severe liver failure (groups Child-Pugh B and Child-Pugh C) than those in mild impairment (Child-Pugh A). Considering the target area under the time-concentration curve (AUC0-24)/MIC ≥4.5 for patients with pulmonary infection, most patients with high-dose (100 mg, every 12 hours) or standard-dose (50 mg, every 12 hours) for tigecycline achieved the target in groups Child-Pugh A, B, and C. Considering the target AUC0-24/MIC ≥6.96 for patients with intra-abdominal infection, when MIC ≤1 mg/L, more than 80% of the patients achieved the target. For an MIC of 2-4 mg/L, only patients with high-dose tigecycline in groups Child-Pugh B and C attained the treatment target. Patients experienced a reduction in fibrinogen values after treatment with tigecycline. In group Child-Pugh C, all 6 patients developed hypofibrinogenemia. Severe hepatic impairment may attain higher PK/PD targets, but carries a high risk of adverse reactions.


Oxidative stress in Parkinson's disease.
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.


Orbitropic Effect in Superfluid 3He B-phase Boundaries.
In this work, we study the influence of orbital viscosity on the evolution of the order-parameter and texture in the B phase of superfluid 3He near a moving boundary. From the redistribution of thermal quasiparticles within the texture, we develop a model which confers a substantial effective mass on the interface, and provides a new mechanism for friction as the boundary moves. We have tested the model against existing data for the motion of an A-B interface whose motion was controlled by a magnetic field. The model allows us to make predictions for the behaviour in experimental situations which involve texture rearrangement arising from motion of the B-phase boundary.


Defining Global Benchmarks in Bariatric Surgery: A Retrospective Multicenter Analysis of Minimally Invasive Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.
To define "best possible" outcomes for bariatric surgery (BS)(Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]). Reference values for optimal surgical outcomes in well-defined low-risk bariatric patients have not been established so far. Consequently, outcome comparison across centers and over time is impeded by heterogeneity in case-mix. Out of 39,424 elective BS performed in 19 high-volume academic centers from 3 continents between June 2012 and May 2017, we identified 4120 RYGB and 1457 SG low-risk cases defined by absence of previous abdominal surgery, concomitant procedures, diabetes mellitus, sleep apnea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, anticoagulation, BMI>50 kg/m and age>65 years. We chose clinically relevant endpoints covering the intra- and postoperative course. Complications were graded by severity using the comprehensive complication index. Benchmark values were defined as the 75th percentile of the participating centers' median values for respective quality indicators. Patients were mainly females (78%), aged 38±11 years, with a baseline BMI 40.8 ± 5.8 kg/m. Over 90 days, 7.2% of RYGB and 6.2% of SG patients presented at least 1 complication and no patients died (mortality in nonbenchmark cases: 0.06%). The most frequent reasons for readmission after 90-days following both procedures were symptomatic cholelithiasis and abdominal pain of unknown origin. Benchmark values for both RYGB and SG at 90-days postoperatively were 5.5% Clavien-Dindo grade ≥IIIa complication rate, 5.5% readmission rate, and comprehensive complication index ≤33.73 in the subgroup of patients presenting at least 1 grade ≥II complication. Benchmark cutoffs targeting perioperative outcomes in BS offer a new tool in surgical quality-metrics and may be implemented in quality-improvement cycle.ClinicalTrials.gov Identifier NCT03440138.


Beliefs about health and illness and health-related behavior among urban women with gestational diabetes mellitus in the south east of China.
The incidence of gestational diabetes among Chinese women is 4.3%. No study has previously been conducted about beliefs and health-related behavior among urban Chinese women with this disease. This article aims to explore beliefs about health and illness and health-related behavior among women in this group in a Chinese sociocultural context. A qualitative exploratory study was conducted and semistructured individual interviews (n = 15) were processed by content analysis. Beliefs about health and illness among these women were foremost attributed to the individual, social, and natural worlds. They feared the negative influence of gestational diabetes, but some of them believed in "letting nature take its course" and "living in the present." Their care-seeking behavior varied between the professional, popular, and folk sectors. They sought a balance between following professionals' advice and avoiding practical difficulties. The beliefs and health-related behavior among them were influenced by Chinese culture, which can sometimes but not always reduce the effect of the disease.