Colonoscopic therapy of acute pseudoobstruction of the colon.
All patients with the diagnosis of acute colonic pseudoobstruction at the University of California, Davis Medical Center from 1979-1985 were reviewed. These 25 patients were initially treated conservatively (nasogastric tube/rectal tube/enemas) and this was successful in eight of 25 patients (32%). The remaining 17 patients (68%) unresponsive to conservative therapy received endoscopic intervention, either colonoscopic suction decompression (CSD) or colonic suction decompression with proximal colonic tube placement (CDT) for continuous decompression. Of the endoscopic procedures performed, 13/17 (76%) resulted in successful acute decompression. Recurrences occurred in 6/13 (45%) (3/7 in the colonoscopic suction decompression group and three of six in the colonic tube placement group). In the 10 failures, six further procedures were attempted, but only one was successful. These patients were then treated conservatively. There were no instances of colonic perforation. Acute pseudoobstruction in our experience is a benign entity that can be safely and successfully treated nonsurgically. Colonoscopic suction decompression is often initially successful but has a high frequency of recurrence. Newer techniques to prevent recurrence, i.e., colonic tube placement, are of potential benefit but presently have technical problems.


Quantification of the Helicality of Helical Molecular Orbitals.
The frontier molecular orbital (MO) topology of linear carbon molecules, such as polyynes, can be visually identified as helices. However, there is no clear way to quantify the helical curvature of these π-MOs, and it is thus challenging to quantify correlations between the helical curvature and molecular properties. In this paper, we develop a method that enables us to compute the helical curvature of MOs based on their nodal planes. Using this method, we define a robust way of quantifying the helical nature of MOs (helicality) by their deviation from a perfect helix. We explore several limiting cases, including polyynes, metallacumulenes, cyclic allenes, and spiroconjugated systems, where the change in helical curvature is subtle yet clearly highlighted with this method. For example, we show that strain only has a minor effect on the helicality of the frontier orbitals of cycloallenes and that the MOs of spiroconjugated systems are close to perfect helices around the spiro-carbon. Our work provides a well-defined method for assessing orbital helicality beyond visual inspection of MO isosurfaces, thus paving the way for future studies of how the helicality of π-MOs affects molecular properties.


Cardiovascular activity in blood-injection-injury phobia during exposure: evidence for diphasic response patterns?
Exposure to feared stimuli in blood-injection-injury (BII)-phobia is thought to elicit a diphasic response pattern, with an initial fight-flight-like cardiovascular activation followed by a marked deactivation and possible fainting (vasovagal syncope). However, studies have remained equivocal on the importance of such patterns. We therefore sought to determine the prevalence and clinical relevance of diphasic responses using criteria that require a true diphasic response to exceed cardiovascular activation of an emotional episode of a negative valence and to exceed deactivation of an emotionally neutral episode. Sixty BII-phobia participants and 20 healthy controls were exposed to surgery, anger and neutral films while measuring heart rate, blood pressure, respiratory pattern, and end-tidal partial pressure of carbon dioxide (as indicator of hyperventilation). Diphasic response patterns were observed in up to 20% of BII-phobia participants and 26.6% of healthy controls for individual cardiovascular parameters. BII-phobia participants with diphasic patterns across multiple parameters showed more fear of injections and blood draws, reported the strongest physical symptoms during the surgery film, and showed the strongest tendency to hyperventilate. Thus, although only a minority of individuals with BII phobia shows diphasic responses, their occurrence indicates significant distress. Respiratory training may add to the treatment of BII phobia patients that show diphasic response patterns.


Silicon-mediated resistance of Arabidopsis against powdery mildew involves mechanisms other than the salicylic acid (SA)-dependent defence pathway.
On absorption by plants, silicon (Si) offers protection against many fungal pathogens, including powdery mildews. The mechanisms by which Si exerts its prophylactic role remain enigmatic, although a prevailing hypothesis suggests that Si positively influences priming. Attempts to decipher Si properties have been limited to plants able to absorb Si, which excludes the model plant Arabidopsis because it lacks Si influx transporters. In this work, we were able to engineer Arabidopsis plants with an Si transporter from wheat (TaLsi1) and to exploit mutants (pad4 and sid2) deficient in salicylic acid (SA)-dependent defence responses to study their phenotypic response and changes in defence expression against Golovinomyces cichoracearum (Gc) following Si treatment. Our results showed that TaLsi1 plants contained significantly more Si and were significantly more resistant to Gc infection than control plants when treated with Si, the first such demonstration in a plant transformed with a heterologous Si transporter. The resistant plants accumulated higher levels of SA and expressed higher levels of transcripts encoding defence genes, thus suggesting a role for Si in the process. However, TaLsi1 pad4 and TaLsi1 sid2 plants were also more resistant to Gc than were pad4 and sid2 plants following Si treatment. Analysis of the resistant phenotypes revealed a significantly reduced production of SA and expression of defence genes comparable with susceptible controls. These results indicate that Si contributes to Arabidopsis defence priming following pathogen infection, but highlight that Si will confer protection even when priming is altered. We conclude that Si-mediated protection involves mechanisms other than SA-dependent defence responses.


Tiamulin feed medication for the maintenance of weight gains in the presence of mycoplasmal pneumonia in swine.
Tiamulin, a semisynthetic antibiotic, was fed to growing pigs and its value in maintaining weight gain and feed efficiency in the face of mycoplasmal pneumonia was determined. Four treatments divided among 64 growing pigs from a conventional pig farm were used to test the effects of tiamulin administered in feed at levels of 10, 20 and 30 ppm. All pigs were artificially infected with Mycoplasma hyopneumoniae. Medication was started on the 14th day after infection (d 0) and continued for 28 d (d 0 to 28). Pigs were continued on test for an additional 14-d period for further observation (d 28 to 42) after the medicated feed was withdrawn. Tiamulin fed at 10, 20 and 30 ppm for 28 d did not cure the mycoplasmal pneumonia. The effect of tiamulin on growth performance was not the same for all periods. During the medication period (d 0 to 28), both daily gain and feed conversion were not significantly affected by dietary tiamulin concentrations. For the post-treatment period (d 28 to 42), tiamulin improved daily gain (P less than .05) and feed conversion (P less than .05) over those of nonmedicated controls, and the responses of both daily gain and feed efficiency increased linearly (P less than .05) as dietary tiamulin levels increased.


[Endoscopic retrograde cholangiography with a single-balloon enteroscope in patients with Roux-en-Y hepatico jejunal anastomosis].
The aim of this retrospective study was to evaluate our experience with using a single-balloon enetroscope for diagnostic and therapeutic endoscopic retrograde cholangiography (ERC) in patients with Roux-en-Y hepatico jejunal anastomosis (HJA). Due to the considerably changed anatomic circumstances after the surgery, ERC is, in comparison to the standard endoscopic retrograde cholangiopancraeaticography (ERCP), significantly more difficult to perform. The sample was followed up from January 2009 to September 2011. The study retrospectively reviewed 14 patients with Roux-en-Y HJA with symptoms of biliary obstruction. A total of 21 ERCs were performed in these 14 Roux-en-Y HJA patients using the single-balloon videoenetroscope Olympus SIF Q 180. Diagnostic ERC cannulation was successful in 11 of the 14 patients (79% success rate for the diagnostic ERC). One of the 11 patients had a normal finding on the ERC. The remaining 10 patients had a pathological finding on ERC that, in one patient (cystic dilatation of bile duct), was subsequently managed surgically. Endoscopic treatment was initiated in the remaining 9 patients (HJA stenosis in 4, choledocholithiasis in 2 and concurrent HJA stenosis and choledocholithiasis in 3) immediately after the diagnostic ERC; the surgery was successful in 8 of the 9 patients (89% success rate for the therapeutic ERC). The performed endoscopic therapeutic procedures included: balloon dilatation of HJA stenosis 9 times (6 patients), choledocholithiasis extraction - 5 times (5 patients), biliary plastic stent placement - 5 times (3 patients), removal of biliary stents placed by us - 5 times (3 patients). We did not observe any complications in our sample of 14 patients. ERC using a single-balloon enteroscope in patients with Roux-Y HJA is significantly more difficult than the standard ERCP due to different post-surgical anatomy. In our sample of patients, we achieved 79% success rate for the diagnostic ERC and 89% success rate for the therapeutic ERC. Additional time should be allowed for the individual procedures. Furthermore, the presence of an anaesthesiologist during these operations (deep analgosedation) is essential. This is a technically very demanding technique that, however, is effective and safe and importantly extends the options available for the management of biliary pathologies in these patients.


[A medical registry of the victims at the centers of catastrophes].
The article discusses the practical significance of medical registry in liquidation of catastrophe consequences. On the basis of summarized experience the authors propose a conception of statistic registry for cases of disaster medicine. They worked out a variant of a record card for the victims of catastrophes. There is a principal scheme for formation of registry information in aid posts and medical establishments.


Transcranial brain stimulation (TMS and tDCS) for post-stroke aphasia rehabilitation: Controversies.
Transcranial brain stimulation (TS) techniques have been investigated for use in the rehabilitation of post-stroke aphasia. According to previous reports, functional recovery by the left hemisphere improves recovery from aphasia, when compared with right hemisphere participation. TS has been applied to stimulate the activity of the left hemisphere or to inhibit homotopic areas in the right hemisphere. Various factors can interfere with the brain's response to TS, including the size and location of the lesion, the time elapsed since the causal event, and individual differences in the hemispheric language dominance pattern. The following questions are discussed in the present article: [a] Is inhibition of the right hemisphere truly beneficial?;[b] Is the transference of the language network to the left hemisphere truly desirable in all patients?;[c] Is the use of TS during the post-stroke subacute phase truly appropriate? Different patterns of neuroplasticity must occur in post-stroke aphasia.


Automatic knee cartilage and bone segmentation using multi-stage convolutional neural networks: data from the osteoarthritis initiative.
Accurate and efficient knee cartilage and bone segmentation are necessary for basic science, clinical trial, and clinical applications. This work tested a multi-stage convolutional neural network framework for MRI image segmentation. Stage 1 of the framework coarsely segments images outputting probabilities of each voxel belonging to the classes of interest: 4 cartilage tissues, 3 bones, 1 background. Stage 2 segments overlapping sub-volumes that include Stage 1 probability maps concatenated to raw image data. Using six fold cross-validation, this framework was tested on two datasets comprising 176 images [88 individuals in the Osteoarthritis Initiative (OAI)] and 60 images (15 healthy young men), respectively. On the OAI segmentation dataset, the framework produces cartilage segmentation accuracies (Dice similarity coefficient) of 0.907 (femoral), 0.876 (medial tibial), 0.913 (lateral tibial), and 0.840 (patellar). Healthy cartilage accuracies are excellent (femoral = 0.938, medial tibial = 0.911, lateral tibial = 0.930, patellar = 0.955). Average surface distances are less than in-plane resolution. Segmentations take 91 ± 11 s per knee. The framework learns to automatically segment knee cartilage tissues and bones from MR images acquired with two sequences, producing efficient, accurate quantifications at varying disease severities.


Microbially Synthesized Polymeric Amyloid Fiber Promotes β-Nanocrystal Formation and Displays Gigapascal Tensile Strength.
The ability of amyloid proteins to form stable β-sheet nanofibrils has made them potential candidates for material innovation in nanotechnology. However, such a nanoscale feature has rarely translated into attractive macroscopic properties for mechanically demanding applications. Here, we present a strategy by fusing amyloid peptides with flexible linkers from spidroin; the resulting polymeric amyloid proteins can be biosynthesized using engineered microbes and wet-spun into macroscopic fibers. Using this strategy, fibers from three different amyloid groups were fabricated. Structural analyses unveil the presence of β-nanocrystals that resemble the cross-β structure of amyloid nanofibrils. These polymeric amyloid fibers have displayed strong and molecular-weight-dependent mechanical properties. Fibers made of a protein polymer containing 128 repeats of the FGAILSS sequence displayed an average ultimate tensile strength of 0.98 ± 0.08 GPa and an average toughness of 161 ± 26 MJ/m3, surpassing most recombinant protein fibers and even some natural spider silk fibers. The design strategy and the biosynthetic approach can be expanded to create numerous functional materials, and the macroscopic amyloid fibers will enable a wide range of mechanically demanding applications.


Hematopoietic stem cell expansion: challenges and opportunities.
Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell population. Although hematopoietic stem cells (HSCs) will rapidly expand after in vivo transplantation, experience from in vitro studies indicates that control of HSPC self-renewal and differentiation in culture remains difficult. Protocols that are based on hematopoietic cytokines have failed to support reliable amplification of immature stem cells in culture, suggesting that additional factors are required. In recent years, several novel factors, including developmental factors and chemical compounds, have been reported to affect HSC self-renewal and improve ex vivo stem cell expansion protocols. Here, we highlight early expansion attempts and review recent development in the extrinsic control of HSPC fate in vitro.


Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation.
Human metapneumovirus (hMPV) is a paramyxovirus that is a common cause of bronchiolitis and pneumonia in children less than five years of age. The hMPV fusion (F) glycoprotein is the primary target of neutralizing antibodies and is thus a critical vaccine antigen. To facilitate structure-based vaccine design, we stabilized the ectodomain of the hMPV F protein in the postfusion conformation and determined its structure to a resolution of 3.3 Å by X-ray crystallography. The structure resembles an elongated cone and is very similar to the postfusion F protein from the related human respiratory syncytial virus (hRSV). In contrast, significant differences were apparent with the postfusion F proteins from other paramyxoviruses, such as human parainfluenza type 3 (hPIV3) and Newcastle disease virus (NDV). The high similarity of hMPV and hRSV postfusion F in two antigenic sites targeted by neutralizing antibodies prompted us to test for antibody cross-reactivity. The widely used monoclonal antibody 101F, which binds to antigenic site IV of hRSV F, was found to cross-react with hMPV postfusion F and neutralize both hRSV and hMPV. Despite the cross-reactivity of 101F and the reported cross-reactivity of two other antibodies, 54G10 and MPE8, we found no detectable cross-reactivity in the polyclonal antibody responses raised in mice against the postfusion forms of either hMPV or hRSV F. The postfusion-stabilized hMPV F protein did, however, elicit high titers of hMPV-neutralizing activity, suggesting that it could serve as an effective subunit vaccine. Structural insights from these studies should be useful for designing novel immunogens able to induce wider cross-reactive antibody responses.


Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis.
The retrogenesis model of Alzheimer's disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.


Wogonin Accelerates Hematoma Clearance and Improves Neurological Outcome via the PPAR-γ Pathway After Intracerebral Hemorrhage.
Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity for which effective treatments are currently lacking. Wogonin is a major flavonoid compound isolated from Scutellaria radix. Accumulating evidence suggests that wogonin plays a crucial role in anti-inflammatory and anti-oxidative stress. Treatment of microglia with nuclear receptor agonists augments the expression of phagocytosis-related genes. However, the neuroprotective effects of wogonin in ICH remain obscure. In this study, we elucidated an innovative mechanism by which wogonin acts to enhance phagocytosis in a murine model of ICH. Wogonin promoted hematoma clearance and improved neurological recovery after ICH by upregulating the expression of Axl, MerTK, CD36, and LAMP2 in perihematomal microglia and BV2 cells. Treatment of a murine model of ICH with wogonin stimulated microglial phagocytosis in vitro. Further, we demonstrated that wogonin dramatically attenuated inflammatory and oxidative stress responses in a murine model of ICH by reducing the expression of pro-inflammatory cytokines and pro-oxidant enzymes such as TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS) after ICH. The effects of wogonin were abolished by administration of the PPAR-γ inhibitor GW9662. In conclusion, our data suggest that wogonin facilitates hematoma clearance and neurobehavioral recovery by targeting PPAR-γ.


HBx activates FasL and mediates HepG2 cell apoptosis through MLK3-MKK7-JNKs signal module.
To investigate the possible mechanism by which hepatitis B virus X protein (HBx) mediates apoptosis of HepG2 cells. HBx expression vector pcDNA3.1-X was transfected into HepG2 cells to establish an HBx high-expression cellular model as pcDNA3.1-X transfected group. The pcDNA3.1-X and pSilencer3.1-shHBX (HBx antagonist) were cotransfected into HepG2 cells to establish an HBx low-expression model as RNAi group. Untransfected HepG2 cells and HepG2 cells transfected with negative control plasmid were used as controls. Apoptosis rate, the expression of Fas/FasL signaling pathway-related proteins and the phosphorylation levels of MLK3, MKK7 and JNKs, which are upstream molecules of death receptor pathways and belong to the family of mitogen-activated protein kinases (MAPKs), were measured in each group. Compared with HepG2 cell group and RNAi group, apoptosis rate, the expression of Fas and FasL proteins, and the activation of MLK3, MKK7 and JNKs were increased in the pcDNA3.1-X transfected group. The activation of JNKs and expression of FasL protein were inhibited in the pcDNA3.1-X transfected group when treated with a known JNK inhibitor, SP600125. When authors treated pcDNA3.1-X transfected group with K252a, a known MLK3 inhibitor, the activation of MLK3, MKK7 and JNKs as well as expression of FasL protein was inhibited. Furthermore, cell apoptosis rate was also significantly declined in the presence of K252a in the pcDNA3.1-X transfected group. HBx can induce HepG2 cell apoptosis via a novel active MLK3-MKK7-JNKs signaling module to upregulate FasL protein expression.


IV antibiotic therapy in the community: clinically effective and cost effective.
This article discusses how the introduction of new ways of working has resulted in a more cost-effective service for the delivery of intravenous (IV) antibiotic therapy in a community setting. When community IV therapy was originally initiated in the trust, the system involved two nurses to check calculations and oversee the administration of IV antibiotic therapy. However, as the demand for IV therapy escalated, and with some patients requiring multiple visits, pressures on community nursing teams created challenges relating to capacity and demand. This service improvement project involved two phases. Phase one examined patient safety and the administration of IV antibiotics by one nurse. Phase two reviewed the administration of IV antibiotic via a timed bolus route. Following the analysis, the implementation of these initiatives demonstrated maximisation of resources, a release of nurses' time to care and improvements to the patient experience.


Predicting optimal transmission investment in malaria parasites.
In vertebrate hosts, malaria parasites face a tradeoff between replicating and the production of transmission stages that can be passed onto mosquitoes. This tradeoff is analogous to growth-reproduction tradeoffs in multicellular organisms. We use a mathematical model tailored to the life cycle and dynamics of malaria parasites to identify allocation strategies that maximize cumulative transmission potential to mosquitoes. We show that plastic strategies can substantially outperform fixed allocation because parasites can achieve greater fitness by investing in proliferation early and delaying the production of transmission stages. Parasites should further benefit from restraining transmission investment later in infection, because such a strategy can help maintain parasite numbers in the face of resource depletion. Early allocation decisions are predicted to have the greatest impact on parasite fitness. If the immune response saturates as parasite numbers increase, parasites should benefit from even longer delays prior to transmission investment. The presence of a competing strain selects for consistently lower levels of transmission investment and dramatically increased exploitation of the red blood cell resource. While we provide a detailed analysis of tradeoffs pertaining to malaria life history, our approach for identifying optimal plastic allocation strategies may be broadly applicable.


Identification by differential display of transcripts regulated during hematopoietic differentiation.
The polymerase chain reaction-based differential display method (DDRT-PCR) was used to identify mRNAs differentially expressed during the maturation of human CD34+ progenitor cells stimulated to differentiate in vitro towards granulomonocytic or erythroid lineages with a mixture of hemopoietins (kit ligand + interleukin 3 + GM-CSF in the absence or presence of erythropoietin, respectively). Three cDNA transcripts (B32, B41, and B56) display differential expression during cytokine-induced maturation of CD34+ cells. These clones have no homology with already-described sequences. Primer extension cofirmed the presence of the corresponding mRNA. The levels of mRNA corresponding to B32 are enhanced in the later phases of the granulomonocytic as well as in the erythroid differentiation of CD34+ cells. The mRNA identified by B41 was induced by a late stage in only granulomonocytic differentiation of CD34+ cells. The mRNA corresponding to B56 was instead present in nonstimulated CD34+ cells, declined in the early stages of differentiation, and reappeared at later stages in cells treated with both combinations of cytokines. Expression of these genes was detected in a number of acute myelogenous leukemias, as well as in some leukemic cell lines. B32 and B41 were downregulated in KG-1 cells induced to differentiate towards the monocytic lineage, whereas the levels of B56 were unchanged. In K562 cells, clones B41 and B56 were downregulated only in the late phases of PMA-induced megakaryocytic differentiation and during erythroid differentiation. B32 was rapidly downregulated when K562 cells were induced to differentiate towards either megakaryocytic or erythroid phenotypes. These transcripts represent novel hematopoietic cDNAs that should prove of value for the study of human blood cells and their disorders.


Iatrogenic medication errors in a paediatric intensive care unit in Durban, South Africa.
Iatrogenic medication errors due to calculation errors are an under-reported concern in children. To determine the incidence and source of iatrogenic medication errors in a paediatric intensive care unit (PICU). A prospective study was conducted in the PICU at Inkosi Albert Luthuli Hospital, Durban, South Africa, over a 3-month period in 2014. Medication-related calculation skills of medical practitioners and nurses were assessed through the voluntary anonymous completion of a questionnaire. Medication errors were recorded either spontaneously or by review of all electronic records of admissions. Errors were classified as delays in the decision to prescribe, prescribing mistakes, dispensing errors and administration issues. Of 25 staff members sampled, only 6 (24.0%) were able to complete all medication calculations accurately, while 44.0% (n=11) were unable to answer three or more questions correctly. Errors most frequently encountered included failure to calculate rates of infusion and the conversion of mL to mEq or mL to mg for potassium, phenobarbitone and digoxin. Of the 117 children admitted, 111 (94.9%) were exposed to at least one medication error. Two or more medication errors occurred in 34.1% of cases. Of the errors, 73.8% were detected on chart review and 26.2% by spontaneous reporting. Overall, 89.2% of errors occurred during prescribing, with 10.0% having a ≥10-fold increase or decrease in dosage calculations. Only 2.7% of medication errors were reported as resulting in adverse events. Therapeutic skills of healthcare professionals working in the PICU need to be improved to decrease iatrogenic medication errors.


[Changes in bone marrow among HIV-positive and HIV-negative parenteral drug addicts].
The aim of the present was to study the cytohistology of the bone marrow in intravenous drug addicts (IVDA) and to analyze the possible differences according to the period of drug addiction. A prospective study was performed in 60 IVDA patients previously untreated and distributed into three groups: 20 seronegative for the human immunodeficiency virus (HIV), 20 patients in a phase of generalized adenopathic infection (GAI) and 20 patients with AIDS. Cytohistologic examination of the bone marrow aspirates showed plasmocytosis and eosinophilia in all the groups. Selective changes were seen in the red series in 20% of the HIV negative patients and in 25% of the GAI group. The prevalence of cytologic changes was greater in those with AIDS, with hypocellular bone marrow being observed in 65% of the patients with coexistent dismyelopoietic changes in 15%. Pathologic structure showed granulomatous lesions of tuberculous etiology in 30% of the patients with AIDS while in the HIV negative and GAI groups these were found in 10% and 5%, respectively. A greater presence of fibrosis and bone marrow hypoplasia was also found in the group with AIDS, than in the other two groups. An increased number of bone marrow changes and progressive bone marrow hypocellularity may be observed on advancement of the clinical stages in intravenous drug addict patients. The incidence of tuberculous granulomas is higher in the AIDS group.


Emerging trends in aggregation induced emissive luminogens as bacterial theranostics.
The emergence and spread of pathogenic bacteria, particularly antibiotic-resistant strains pose grave global concerns worldwide, which demand for the rapid development of highly selective and sensitive strategies for specific bacterial detection, identification, imaging and therapy. The fascinating feature of aggregation-induced emissive molecules (AIEgens) to display fluorescence in aggregate form can be suitably coupled with nanotechnology for developing theranostic AIE dots that can offer convenient and customised functions such as sensing, imaging, detection, discrimination and cell kill of different bacterial types. The initial section of the article reveals the necessity for incorporating diagnostic imaging with antibacterial therapy, while the latter part delivers mechanistic insights on the benefits of AIE fluorophores in theranostic applications. Further, the review illustrates the recent advancements of AIEgens as theranostic nanolights in bacterial detection, identification and eradication. The review is organised according to the different classes of AIE-active bacterial theranostics such as carrier-free nanoprodrugs, nanomachines for synergistic imaging-guided cancer treatment and bacterial kill, AIE polymers, bioconjugates and nanoparticle carriers. By elucidating their design principles and applications, as well as highlighting the recent trends and perspectives that can be further explored, we hope to instill more research interest in AIE bacterial theranostics for future translational research.HighlightsCombination of aggregation induced emissive fluorophores and nanotechnology for developing bacterial theranostics.AIE theranostics with customised functions for bacterial imaging, detection, discrimination and cell kill.


The complete mitochondrial genome of Echinolaelaps fukienensis provide insights into phylogeny and rearrangement in the superfamily Dermanyssoidea.
Echinolaelaps fukienensis is the dominant mite species parasitic on the body surface of the genus Niviventer. The mitochondrial genome (mitogenome) has its own independent genetic material and genetic system, and is now widely used in population genetics, genealogical biogeography, phylogeny and molecular evolution studies. Species diversity of the superfamily Dermanyssoidea is very rich, but its mitogenomes AT content is high, and it is difficult to amplify the complete mitogenome by routine PCR. To date, we have only obtained the mitogenomes of 6 species, scarcity on sequence data has greatly impeded the studies in the superfamily Dermanyssoidea. Echinolaelaps fukienensis were collected in 2019 from the body surface of Niviventer confucianus (Rodentia, Muridae) in Yunnan Province. The E. fukienensis mitogenome was determined and analyzed for the first time using the Illumina Novoseq 6000 platform. Phylogenetic analyses of the superfamily Dermanyssoidea were conducted based on the entire mitogenome sequences. The E. fukienensis mitogenome was 14,402 bp, which is known the smallest genome of the superfamily Dermanyssoidea, encoding a total of 37 genes, including 13 PCGs, 22 tRNAs, 2 rRNAs and 1 control region. Most protein-coding genes use ATN as the start codon and TAN as the stop codon. AT and GC skew of atp8 genes in E. fukienensis were both 0. The average length of 22 tRNA genes of E. fukienensis was 64 bp, and secondary structures of tRNAs showed base mismatches and missing D-arms in many places. Compared with gene arrangement pattern of the hypothetical ancestor of arthropods, the E. fukienensis mitogenome shows a novel arrangement pattern. Phylogenetic tree supported the monophyly of the superfamily Dermanyssoidea. Echinolaelaps fukienensis being the least genetic distant (0.2762) and most closely related to Varroa destructor. This study analyzed comprehensive the structure and evolution of the E. fukienensis mitogenome for the first time, enriches molecular data of the genus Echinolaelaps, which will contribute to further understand phylogeny and rearrangement patterns of the superfamily Dermanyssoidea.


Quantitative Assessment of the Cryolipolysis Method for Body Contouring in Asian Patients.
Cryolipolysis has been demonstrated to be a safe and efficient non-invasive treatment modality for reducing subcutaneous discrete areas of fat; however, only limited studies have focused on body contouring in Asian patients. The present work focuses on the quantitative assessment of the cryolipolysis method for body contouring in Asian patients. The retrospective study evaluated the medical records of 4122 patients with body contouring who underwent cryolipolysis treatment in multiple centers across Japan from January 2019 to June 2019. We evaluated the demographic profiles, treatment areas, and safety assessments among these 4122 patients. The effectiveness of the treatment was assessed in 146 patients at one of the clinics, Shonan Beauty Clinic, out of which 54 and 27 had treatments in the abdomen and upper arm areas, respectively. Clinical outcomes were assessed based on patient surveys, circumference measurements, and assessment of photographs. Evaluation of choice for treatment area suggested that men generally focused more on the surrounding areas of the abdomen, while women even had options for the abdomen and the upper arm. No long-term side effects were observed during the study period. There was a significant reduction in the circumference of both the abdomen and upper arm areas (P < 0.05). Additionally, 16.7% and 18.5% of patients who had received treatment on their abdomen and upper arm, respectively, returned for the next sessions within six months. Patients who had received treatment on their upper arms were more satisfied in the categories of pain and bruising and treatment effectiveness compared to those who had received treatment on their abdomen. Based on the results obtained in this retrospective study on Asian patients, it can be stated that cryolipolysis is a safe and well-tolerated nonsurgical fat-reduction procedure. Clinical effectiveness can be consistently achieved with proper patient evaluation and patient satisfaction.


Receptor effects of cetirizine.
First-generation H1-antagonist antihistamines such as hydroxyzine have a significant ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but does not cause sedation. This lack of CNS effects may be due to cetirizine's greater selectivity or potency at H1 receptors in the brain, compared with its effects at the receptors involved in sedation, or it may result from the agent's relative exclusion from the CNS compartment. We compared cetirizine's activity at central H1 sites with the activity of hydroxyzine and terfenadine. We also compared the abilities of cetirizine and three other antihistamines to cross the blood-brain barrier. We found the drugs' potency at H1 receptors in the CNS to be similar to their activities in other tissues. However, their selectivity varied widely. Cetirizine, in fact, failed to bind at any of the receptors investigated except H1 sites, even at concentrations as high as 10 micron. Both hydroxyzine and D-chlorpheniramine crossed the blood-brain barrier in significant amounts. Terfenadine did so to a much lesser extent, and cetirizine passed into the CNS only half as readily as terfenadine. We suggest that cetirizine's reduced incidence of sedative side effects may stem partly from its selectivity for H1 receptors over sites involved in sedation, and partly from its relative exclusion from the CNS.


Evolutionary degeneration of septins into pseudoGTPases: impacts on a hetero-oligomeric assembly interface.
The septin family of eukaryotic proteins comprises distinct classes of sequence-related monomers that associate in a defined order into linear hetero-oligomers, which are capable of polymerizing into cytoskeletal filaments. Like actin and ⍺ and β tubulin, most septin monomers require binding of a nucleotide at a monomer-monomer interface (the septin "G" interface) for assembly into higher-order structures. Like ⍺ and β tubulin, where GTP is bound by both subunits but only the GTP at the ⍺-β interface is subject to hydrolysis, the capacity of certain septin monomers to hydrolyze their bound GTP has been lost during evolution. Thus, within septin hetero-oligomers and filaments, certain monomers remain permanently GTP-bound. Unlike tubulins, loss of septin GTPase activity-creating septin "pseudoGTPases"-occurred multiple times in independent evolutionary trajectories, accompanied in some cases by non-conservative substitutions in highly conserved residues in the nucleotide-binding pocket. Here, we used recent septin crystal structures, AlphaFold-generated models, phylogenetics and in silico nucleotide docking to investigate how in some organisms the septin G interface evolved to accommodate changes in nucleotide occupancy. Our analysis suggests that yeast septin monomers expressed only during meiosis and sporulation, when GTP is scarce, are evolving rapidly and might not bind GTP or GDP. Moreover, the G dimerization partners of these sporulation-specific septins appear to carry compensatory changes in residues that form contacts at the G interface to help retain stability despite the absence of bound GDP or GTP in the facing subunit. During septin evolution in nematodes, apparent loss of GTPase activity was also accompanied by changes in predicted G interface contacts. Overall, our observations support the conclusion that the primary function of nucleotide binding and hydrolysis by septins is to ensure formation of G interfaces that impose the proper subunit-subunit order within the hetero-oligomer.


Role of palatability on meal-induced thermogenesis in human subjects.
To study the possible participation of food-induced sensory stimulation on meal thermogenesis an experiment was performed with eight female subjects. On alternate days subjects were fed either a highly palatable meal (HPM), containing 710 calories, or a nonpalatable meal (NPM). The NPM was prepared by mixing all the ingredients of the HPM and was presented to the subjects as a desiccated biscuit. The subjects were not informed about the composition of the NPM, which they rated as tasteless and unappetizing. The increase in O2 consumption was approximately 20% during the 90 min following the HPM compared with 12% with the NPM (P less than 0.01). With comparable increases in plasma glucose, plasma insulin level was significantly (P less than 0.01) lower following NPM ingestion than with ingestion of the HPM. At that time a significant increase in plasma norepinephrine was also observed but only following ingestion of the HPM. It would appear that both central sensory stimulation or plasma insulin level, as affected by food palatability, could be considered at this time as possible activators of the increased sympathetic activity observed following ingestion of the HPM. It is suggested that a part of meal thermogenesis is due to food palatability and that the concomitant activation of the sympathetic system may be related to this action.


Structure of calmodulin complexed with an olfactory CNG channel fragment and role of the central linker: residual dipolar couplings to evaluate calmodulin binding modes outside the kinase family.
The NMR high-resolution structure of calmodulin complexed with a fragment of the olfactory cyclic-nucleotide gated channel is described. This structure shows features that are unique for this complex, including an active role of the linker connecting the N- and C-lobes of calmodulin upon binding of the peptide. Such linker is not only involved in the formation of an hydrophobic pocket to accommodate a bulky peptide residue, but it also provides a positively charged region complementary to a negative charge of the target. This complex of calmodulin with a target not belonging to the kinase family was used to test the residual dipolar coupling (RDC) approach for the determination of calmodulin binding modes to peptides. Although the complex here characterized belongs to the (1--14) family, high Q values were obtained with all the 1:1 complexes for which crystalline structures are available. Reduction of the RDC data set used for the correlation analysis to structured regions of the complex allowed a clear identification of the binding mode. Excluded regions comprise calcium binding loops and loops connecting the EF-hand motifs.


Cell-cell interactions at the ectoplasmic specialization in the testis.
During spermatogenesis, the movement of developing germ cells across the seminiferous epithelium involves the restructuring of adherens junctions that form between Sertoli cells and between Sertoli and germ cells such as the ectoplasmic specialization (ES). At the ultrastructural level, the ES has been thoroughly studied for the past three decades. Until recently, however, relatively little has been known about the molecular architecture, not to mention the mechanism, that regulates the ES. Recent findings in the field have highlighted several areas of research that deserve attention in future studies. For example, proteins that constitute the ES can be targeted to compromise cell adhesion. This approach will not only provide a better understanding of ES dynamics, but also will yield innovative approaches for the development of male contraceptives.


Dietary alpha-linolenic acid deficiency in the rat. I. Effects on reproduction and postnatal growth.
The effects of a dietary alpha-linolenic acid (18 : 3 n-3) deficiency on reproduction and postnatal growth in rats were studied during 3 successive gestations and 4 successive generations. Female rats received respectively a semi-synthetic diet in which the lipids were incorporated either as sunflower oil at 1.5% (deficient diet) or as soya oil at 1.87% (control diet). Both diets supplied the same amount of linoleic acid (18 : 2 n-6) (940 mg/100 g of diet), but the sunflower oil supplied 22 times less alpha-linolenic acid than the soya diet (6 mg vs 130 mg/100 g of diet). The results showed that, in our experimental conditions, the alpha-linolenic acid deficiency had no effect on fecundity (% of pregnant females), fertility (number of pups/litter), pup birth weight, food intake and weight of pregnant or lactating females, or pup growth during suckling. However, this deficiency did cause abnormally high rates of perinatal mortality from birth to postpartum day 3, namely on the average, for successive gestations: 18.5% in deficient pups vs 5.2% in the controls, and for successive generations: 16.6% in deficient pups vs 5.3% in the controls. Rat n-3 PUFA requirement during reproduction has been discussed; it appears to be more than 100 mg/100 g of feed. But this need should also be estimated in relation to n-6 PUFA supply; for female rats during reproduction, the ratio n-6: n-3 should be less than 10.


Clinical issues regarding relapsing aspergillosis and the efficacy of secondary antifungal prophylaxis in patients with hematological malignancies.
Advancements in early diagnosis and the introduction of effective agents have improved the rates of response of aspergillosis to primary antifungal therapy. These changes allow the subsequent continuation of cytotoxic chemotherapy and/or performance of hematopoietic stem cell transplantation in an increasing number of patients with hematological malignancies. These developments have increased interest in secondary prophylaxis of aspergillosis, because the resumption of myelotoxic chemotherapy in these patients is associated with high rates of relapse of this opportunistic mycosis in the absence of prophylaxis. However, the risk factors for relapsing invasive aspergillosis and the strategies for reducing risk are not well defined. Furthermore, differentiating aspergillosis relapse from reinfection with a new Aspergillus isolate is problematic when using the available laboratory tools. We summarize the existing knowledge regarding the pathogenesis of, risk factors for, and natural history of relapsing invasive aspergillosis and review the limited data regarding the role of secondary antifungal prophylaxis.


Psychometric properties of a modified version of the Caregiver Reaction Assessment Scale measuring caregiving and post-caregiving reactions of caregivers of cancer patients.
Most care received by cancer patients is provided in the community by informal or unpaid caregivers. The unrelenting care demands can lead to physical, emotional, social, and financial reactions; furthermore, studies indicate that the effects of caregiving may endure after the patient's death. A need therefore exists for instruments measuring both caregiving and post-caregiving reactions. Among available instruments, the Caregiver Reaction Assessment (CRA) is a multidimensional, 5-factor measure designed to assess the negative and positive aspects of caregiving. The current study examined the psychometric properties and factor structure of responses to a modified Hebrew version of the CRA aimed at measuring caregiving and post-caregiving reactions. Although the scale was modified, it was assumed that, similar to the original CRA, a 5-factor structure would be supported by means of confirmatory factor analysis. A total of 236 bereaved primary caregivers of cancer patients from central and southern regions of Israel were recruited over a period of 18 months. As hypothesized, results provide support for a 5-factor structure of responses to this modified version of the CRA. The concurrent validity of responses to the scale was also supported. Replication of the findings with randomly derived and larger sample sizes is needed.


The relationship between cytochondria and myofibrils in pigeon skeletal muscle.
In pigeon breast muscle the mitochondria are the principal site of oxidative metabolism, whereas the myofibrils are incapable of oxidizing intermediates of the Krebs cycle. The mitochondria contain the oxidative enzymes, and the sarcosomes are associated with a factor which accelerates the mitochondrial oxidative rate. The maintenance of myofibrillar contractility and structure is closely correlated with preservation of mitochondrial oxidative capacity and structure. By use of fluoride and dinitrophenol the connection between mitochondrial metabolism and myofibrillar behavior is shown to occur through the process of oxidative phosphorylation.


Concentrated Sunlight for Materials Synthesis and Diagnostics.
Herein, the use of highly concentrated sunlight for materials science research is reviewed. Specific research directions include: (1) the generation of inorganic nanostructures, some of which had eluded experimental realization with conventional synthetic processes, and (2) elucidating the processes governing the degradation of organic and perovskite-based photovoltaic materials and devices, along with accelerated assessment of their stability. Both approaches employ solar concentrators capable of producing flux densities exceeding those of terrestrial solar radiation by up to three orders of magnitude, and are geared toward either creating extensive ultrahot reactor conditions conducive to the rapid, safe synthesis of unusual nanomaterials or judiciously interrogating photovoltaic devices.


Effectiveness of at-home skin temperature monitoring in reducing the incidence of foot ulcer recurrence in people with diabetes: a multicenter randomized controlled trial (DIATEMP).
The skin of people with diabetic foot disease is thought to heat up from ambulatory activity before it breaks down into ulceration. This allows for early recognition of imminent ulcers. We assessed whether at-home monitoring of plantar foot skin temperature can help prevent ulcer recurrence in diabetes. In this parallel-group outcome-assessor-blinded multicenter randomized controlled trial (7 hospitals, 4 podiatry practices), we randomly assigned people with diabetes, neuropathy, foot ulcer history (<4 years, n=295), or Charcot's neuro-arthropathy (n=9) to usual care (ie, podiatric treatment, education, and therapeutic footwear) or usual care plus measuring skin temperatures at 6-8 plantar sites per foot each day (enhanced therapy). If ∆T>2.2°C between corresponding sites on the left and right foot for two consecutive days, participants were instructed to reduce ambulatory activity until this hotspot disappeared and contact their podiatrist. Primary outcome was ulcer recurrence in 18 months on the plantar foot, interdigital, or medial/lateral/anterior forefoot surfaces; secondary outcome was ulcer recurrence at any foot site. On the basis of intention-to-treat, 44 of 151 (29.1%) participants in enhanced therapy and 57 of 153 (37.3%) in usual care had ulcer recurrence at a primary outcome site (RR: 0.782 (95%CI 0.566 to 1.080), p=0.133). Of the 83 participants in enhanced therapy who measured a hotspot, the 24 subsequently reducing their ambulatory activity had significantly fewer ulcer recurrences (n=3) than those in usual care (RR: 0.336 (95% CI 0.114 to 0.986), p=0.017). Enhanced therapy was effective over usual care for ulcer recurrence at any foot site (RR: 0.760 (95% CI 0.579 to 0.997), p=0.046). At-home foot temperature monitoring does not significantly reduce incidence of diabetic foot ulcer recurrence at or adjacent to measurement sites over usual care, unless participants reduce ambulatory activity when hotspots are found, or when aiming to prevent ulcers at any foot site. NTR5403.


[Hyperprolactinemia. Study of a current topic].
This recapitulative study presents an integral synthesis of this important subject which during the last years has become more important, particularly regarding drugs for its control, since the studies of Chiari Fromel until now. The idea is to present a didactic contribution for the gyneco-obstetrician which will become more important and useful in the treatment of patients with this problem.


In vitro and tissue culture methods for analysis of translation initiation on the endoplasmic reticulum.
For mRNAs encoding secretory and integral membrane proteins, translation initiation is thought to begin a process of mRNA localization where mRNA/ribosome/nascent chain complexes (RNCs) are trafficked from the cytosol compartment to the endoplasmic reticulum (ER). At the ER membrane, RNCs bind to a protein-conducting channel via the large ribosomal subunit and protein translocation ensues through coupling of the ribosomal nascent protein exit site with the protein-conducting channel. At the termination of translation, ribosomal subunits are thought to dissociate from the ER to return to a common cytoplasmic pool and participate in additional cycles of initiation, translation, targeting, termination, and ER membrane release. Experimental evidence has demonstrated that ER-membrane ribosomes are capable of de novo initiation, that mRNA partitioning to the ER membrane does not, per se, require translation of an encoded signal sequence, and that ribosomal subunit dissociation from the ER membrane is not obligatorily coupled to protein synthesis termination. These findings suggest that the cycle of protein synthesis-initiation, elongation, and termination-can occur on the two-dimensional plane of the ER membrane and challenge current views on the subcellular restriction of translation initiation to the cytosol, the role of the ribosome cycle in partitioning mRNA between the cytosol and ER, and the in vivo basis for termination-induced ribosomal subunit dissociation. In the following chapter, we provide detailed experimental methods to study protein synthesis initiation on the ER membrane.


Use of non-invasive ventilation in cerebral palsy.
Patients with cerebral palsy (CP), especially those at the severe end of the spectrum (Gross Motor Function Classification System levels IV-V equivalent), frequently suffer from sleep disturbance and sleep-disordered breathing (SDB). Non-invasive ventilation (NIV) is increasingly used in this patient group, albeit with little published evidence of its effectiveness in CP. This article aims to review the current evidence in the use of NIV in children with CP, highlighting areas of uncertainties, as well as the balance of potential risks, challenges and benefits. We would also share our experience and practical considerations in using NIV to manage SDB in this group of patients. Between January 2010 and December 2016, 21 patients (median age 11.1 (range 1.7-16.1) years) with CP were initiated on NIV at Great Ormond Street Hospital for Children following diagnosis of moderate to severe SDB on cardiorespiratory polygraphy. Over half of our patients with CP (n=11) failed to establish on NIV either due to intolerance of mask and/or ventilation pressure at the initial trial in hospital, or poor adherence during follow-up, in contrast to the overall failure rate of 8.7% among total patient population commenced on NIV. Children with CP constitute a relatively small but challenging group of patients. Decision to undertake NIV should be individualised, based on benefit outweighing the risk and burden of the treatment.


Cancer survivorship and aging : moving the science forward.
Given the high incidence and prevalence of cancer in older adults and the anticipated growth of this population over the next few decades, oncologists, geriatricians, and primary care providers will be challenged to provide timely and appropriate post-treatment care to a diverse population of older cancer survivors. To the authors' knowledge to date, few post-treatment epidemiologic or clinical trial studies have investigated the mental, social, and physical health issues among older cancer survivors. For this article, the authors reviewed the behavioral oncology, gerontology, geriatric, and psychology literature on cancer survivorship and aging. This report highlights several methodologic challenges that investigators face when conducting epidemiologic and cancer clinical trial research with older cancer survivors after treatment. These challenges must be considered and overcome to develop an informative body of scientific knowledge to address the post-treatment healthcare needs of this growing population. Future research directions, new models of care, and the need for transdisciplinary approaches are discussed.


Chemical and enzymic studies on the characterization of intermediates during the removal of the 14alpha-methyl group in cholesterol biosynthesis. The use of 32-functionalized lanostane derivatives.
By using cell-free preparations of rat liver it was shown that the removal of the 14alpha-methyl group (C-32) of steroids containing either a delta7(8) or a delta8(9) double bond is attended exclusively by the formation of the corresponding 7,14- and 8,14-dienes respectively (structures of types III and VIII). Cumulative evidence from a variety of experimental approaches had led to the deduction that delta8(14)-steroids are not involved as intermediates on the major pathway of cholesterol biosynthesis. The metabolism of [32-3H]lanost-7-ene-3beta,32-diol (structure of type I) results in the formation of radioactive formic acid, no labelled formaldehyde being formed. By using appropriately labelled species of the compound (I) it was found that the release of formic acid and the formation of 4,4-dimethylcholesta-7,14-dien-3beta-ol (strurcture of type III) were closely linked processes, and that in the conversion of compound (I) into compound (III), 3-beta-hydroxylanost-7-en-32-al (II) is an obligatory intermediate. Both the conversion of lanost-7-ene-3beta,32-diol (I) into 3beta-hydroxylanost-7-en-32-al (II) and the further metabolism of the latter (II) to 4,4-dimethylcholesta-7,14-dien-3beta-ol (III) exhibited a requirement for NADPH and O2. This suggests that the oxidation of the 32-hydroxy group of compound (I) to the aldehyde group of compound (II) does not occur by the conventional alcohol dehydrogenase type of reaction, but may proceed by a novel mechanism involving the intermediacy of a gem-diol. A detailed overall pathway for the 14alpha-demethylation in cholesterol biosynthesis is considered, and proposals about the mechanism of individual steps in the pathway are made.


TNFα from classically activated macrophages accentuates epithelial to mesenchymal transition in obliterative bronchiolitis.
Bronchiolitis obliterans syndrome is characterized by fibrotic obliteration of small airways which severely impairs graft function and survival after lung transplantation. Bronchial epithelial cells from the transplanted lung can undergo epithelial to mesenchymal transition and this can be accentuated by activated macrophages. Macrophages demonstrate significant plasticity and change phenotype in response to their microenvironment. In this study we aimed to identify secretory products from macrophages that might be therapeutic targets for limiting the inflammatory accentuation of epithelial to mesenchymal transition in bronchiolitis obliterans syndrome. TNFα, IL-1β and IL-8 are elevated in bronchoalveolar lavage from lung transplant patients prior to diagnosis of bronchiolitis obliterans syndrome. Classically activated macrophages secrete more TNFα and IL-1β than alternatively activated macrophages and dramatically accentuate TGF-β1-driven epithelial to mesenchymal transition in bronchial epithelial cells isolated from lung transplant patients. Blocking TNFα, but not IL-1β, inhibits the accentuation of epithelial to mesenchymal transition. In a pilot unblinded therapeutic intervention in five patients with progressive bronchiolitis obliterans syndrome, anti-TNFα treatment improved forced expiratory volume in 1 second and 6-min walk distances in four patients. Our data identify TNFα as a potential new therapeutic target in bronchiolitis obliterans syndrome deserving of a randomized placebo controlled clinical trial.


The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining.
The basolateral complex of the amygdala (BLA) is critical for the acquisition and expression of Pavlovian fear conditioning in rats. Nonetheless, rats with neurotoxic BLA lesions can acquire conditional fear after overtraining (75 trials). The capacity of rats with BLA lesions to acquire fear memory may be mediated by the central nucleus of the amygdala (CEA). To examine this issue, we examined the influence of neurotoxic CEA lesions or reversible inactivation of the CEA on the acquisition and expression of conditional freezing after overtraining in rats. Rats with pretraining CEA lesions (whether alone or in combination with BLA lesions) did not acquire conditional freezing to either the conditioning context or an auditory conditional stimulus after extensive overtraining. Similarly, post-training lesions of the CEA or BLA prevented the expression of overtrained fear. Lastly, muscimol infusions into the CEA prevented both the acquisition and the expression of overtrained fear, demonstrating that the effects of CEA lesions are not likely due to the destruction of en passant axons. These results suggest that the CEA is essential for conditional freezing after Pavlovian fear conditioning. Moreover, overtraining may engage a compensatory fear conditioning circuit involving the CEA in animals with damage to the BLA.


Optical bistable switching action of Si high-Q photonic-crystal nanocavities.
We have demonstrated all-optical bistable switching operation of resonant-tunnelling devices with ultra-small high-Q Si photonic-crystal nanocavities. Due to their high Q/V ratio, the switching energy is extremely small in comparison with that of conventional devices using the same optical nonlinear mechanism. We also show that they exhibit all-opticaltransistor action by using two resonant modes. These ultrasmall unique nonlinear bistable devices have potentials to function as various signal processing functions in photonic-crystal-based optical-circuits.


Growth Differentiation Factor-8 Decreases StAR Expression Through ALK5-Mediated Smad3 and ERK1/2 Signaling Pathways in Luteinized Human Granulosa Cells.
Growth differentiation factor-8 (GDF-8) has been recently shown to be expressed in human granulosa cells, and the mature form of GDF-8 protein can be detected in the follicular fluid. However, the biological function and significance of this growth factor in the human ovary remains to be determined. Here, we investigated the effects of GDF-8 on steroidogenic enzyme expression and the potential mechanisms of action in luteinized human granulosa cells. We demonstrated that treatment with GDF-8 did not affect the mRNA levels of P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase, whereas it significantly down-regulated steroidogenic acute regulatory protein (StAR) expression and decreased progesterone production. The suppressive effect of GDF-8 on StAR expression was abolished by the inhibition of the TGF-β type I receptor. In addition, treatment with GDF-8 activated both Smad2/3 and ERK1/2 signaling pathways. Furthermore, knockdown of activin receptor-like kinase 5 reversed the effects of GDF-8 on Smad2/3 phosphorylation and StAR expression. The inhibition of Smad3 or ERK1/2 signaling pathways attenuated the GDF-8-induced down-regulation of StAR and production of progesterone. Interestingly, the concentrations of GDF-8 were negatively correlated with those of progesterone in human follicular fluid. These results indicate a novel autocrine function of GDF-8 to down-regulate StAR expression and decrease progesterone production in luteinized human granulosa cells, most likely through activin receptor-like kinase 5-mediated Smad3 and ERK1/2 signaling pathways. Our findings suggest that granulosa cells might play a critical role in the regulation of progesterone production to prevent premature luteinization during the final stage of folliculogenesis.


Effects of caffeine administration on sedation and respiratory parameters in patients recovering from anesthesia.
Caffeine has been shown to enhance the speed of recovery from general anesthesia in murine models, though data in human patients is lacking. This is a retrospective review of intravenous caffeine administration (median dose 150 [125, 250] mg) to 151 heavily sedated patients in the post-anesthesia recovery area, to determine the association between caffeine administration and changes in sedation score, respiratory rate, and oxyhemoglobin saturation. Richmond Agitation-Sedation Scale (RASS) score, respiratory rate, and oxyhemoglobin saturation values were obtained during the 90-minute period prior to and following caffeine administration. Generalized estimating equations (GEE) with explanatory variables of time, caffeine, and the time-by-caffeine interaction were created to assess changes in the variables of interest after caffeine administration. Following the administration of caffeine, the RASS scores increased (estimate = 0.57, SE = 0.14, p < 0.001) but a trend over time or in the interaction effect was not observed, suggesting that the changes in RASS were not solely due to the recovery from anesthesia over time. No association was found between caffeine administration and changes in respiratory parameters. No adverse cardiac events were observed. Our data suggests that intravenous caffeine may enhance the speed of recovery following general anesthesia, though future prospective trials are necessary to define the optimal dose and timing of administration.


Evidence for a polysaccharide-binding domain in Hormoconis resinae glucoamylase P: effects of its proteolytic removal on substrate specificity and inhibition by beta-cyclodextrin.
The hydrolysis of soluble starch, raw starch and pullulan with recombinant glucoamylase P from Hormoconis resinae was competitively inhibited by beta-cyclodextrin with apparent Ki values of 190 microM, 13 microM and 1.4 microM, respectively. Inhibition of dextran hydrolysis was partial: a maximum inhibition of 22% was achieved with a dextran concentration of 0.3 x Km and up to 4 mM beta-cyclodextrin. Hydrolysis of short oligosaccharides was not inhibited by beta-cyclodextrin at levels up to 20 mM. The enzyme bound to raw starch at pH 4.3 and 4 degrees C with an association constant of 3.4 x 10(5) M-1. Sequence alignment studies showed raw-starch-binding consensus amino acids in the C-terminal part of glucoamylase P. Partial hydrolysis with papain resulted in degradation of deglycosylated glucoamylase P into three fragments of 53, 51 and 14 kDa, respectively, as estimated by SDS-PAGE. The amino-terminal sequences of the 51 and 53 kDa fragments were identical with that of native glucoamylase P. The amino terminus of the 14 kDa fragment (Ser-Ser-X-Gln-Val-Ser-), corresponded to the sequence starting at residue 474 of intact glucoamylase P. Kinetic measurements of truncated glucoamylase P showed changes in the Km values of larger polysaccharides, but no changes in kcat values compared to the intact enzyme. It was concluded that glucoamylase P contains a catalytic core domain and a raw-starch-binding domain involved in inhibition of polysaccharide hydrolysis by beta-cyclodextrin.


Localization of Eutr2, a locus controlling susceptibility to DES-induced uterine inflammation and pyometritis, to RNO5 using a congenic rat strain.
In some rat strains chronic administration of exogenous estrogens induces pyometritis, an inflammation of the uterus associated with infection, suggesting that there is genetic variation in susceptibility to estrogen-induced inflammation and pyometritis. In this article we report that following 10 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), Fisher 344 (F344) rats exhibit modest uterine inflammation and a 0% incidence of pyometritis. By contrast, under identical experimental conditions, Brown Norway (BN) rats exhibit significant inflammation and a 100% incidence of pyometritis. Similarly, we also observed profound uterine inflammation and a 100% incidence of pyometritis in a congenic rat strain in which a segment of RNO5 from the BN strain is carried on the F344 strain. These data suggest that a locus on RNO5 controls both the magnitude of DES-induced uterine inflammation and susceptibility to DES-induced pyometritis. This locus, designated Eutr2, resides within the same segment of RNO5 as the Eutr1 locus, which confers susceptibility to E2-induced pyometritis in an F2 population generated in a cross between the BN and August x Copenhagen 9935, Irish (ACI) strains.


Fc gamma receptor glycosylation modulates the binding of IgG glycoforms: a requirement for stable antibody interactions.
FcγRs play a critical role in the immune response following recognition of invading particles and tumor associated antigens by circulating antibodies. In the present study we investigated the role of FcγR glycosylation in the IgG interaction and observed a stabilizing role for receptor N-glycans. We performed a complete glycan analysis of the recombinant FcγRs (FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa(Phe158/Val158), and FcγRIIIb) expressed in human cells and demonstrate that receptor glycosylation is complex and varied between receptors. We used surface plasmon resonance to establish binding patterns between rituximab and all receptors. Complex binding was observed for FcγRIa and FcγRIIIa. The IgG-FcγR interaction was further investigated using a combination of kinetic experiments and enzymatically deglycosylated FcγRIa and FcγRIIIa(Phe158/Val158) receptors in an attempt to determine the underlying binding mechanism. We observed that antibody binding levels decreased for deglycosylated receptors, and at the same time, binding kinetics were altered and showed a more rapid approach to steady state, followed by an increase in the antibody dissociation rate. Binding of rituximab to deglycosylated FcγRIIIa(Phe158) was now consistent with a 1:1 binding mechanism, while binding of rituximab to FcγRIIIa(Val158) remained heterogeneous. Kinetic data support a complex binding mechanism, involving heterogeneity in both antibody and receptor, where fucosylated and afucosylated antibody forms compete in receptor binding and in receptor molecules where heterogeneity in receptor glycosylation plays an important role. The exact nature of receptor glycans involved in IgG binding remains unclear and determination of rate and affinity constants are challenging. Here, the use of more extended competition experiments appear promising and suggest that it may be possible to determine dissociation rate constants for high affinity afucosylated antibodies without the need to purify or express such variants. The data described provide further insight into the complexity of the IgG-FcγR interaction and the influence of FcγR glycosylation.


Proton radiation therapy for clivus chordoma--case report.
A 57-year-old male with clival chordoma developed severe hoarseness, dysphagia, and dysphonia 1 month after a second removal of the tumor. Magnetic resonance imaging demonstrated a mass 10 cm in diameter in the region of the middle clivus enhanced inhomogeneously by gadolinium-diethylenetriaminepentaacetic acid, and a defect in the skull base. There was evidence of compression of the anterior surface of the pons. He received proton irradiation employing a pair of parallel opposed lateral proton beams. The dose aimed at the tumor mass was 75.5 Gy, to the pharyngeal wall less than 38 Gy, and to the anterior portion of the pons less than 30 Gy. Time dose and fractionation factor was calculated at 148. Thirty-one months following treatment, he was free of clinical neurological sequelae. Proton therapy should be considered in treatment planning following initial surgical removal or for inoperable clivus chordoma.


In and out of Madagascar: dispersal to peripheral islands, insular speciation and diversification of Indian Ocean daisy trees (Psiadia, Asteraceae).
Madagascar is surrounded by archipelagos varying widely in origin, age and structure. Although small and geologically young, these archipelagos have accumulated disproportionate numbers of unique lineages in comparison to Madagascar, highlighting the role of waif-dispersal and rapid in situ diversification processes in generating endemic biodiversity. We reconstruct the evolutionary and biogeographical history of the genus Psiadia (Asteraceae), a plant genus with near equal numbers of species in Madagascar and surrounding islands. Analyzing patterns and processes of diversification, we explain species accumulation on peripheral islands and aim to offer new insights on the origin and potential causes for diversification in the Madagascar and Indian Ocean Islands biodiversity hotspot. Our results provide support for an African origin of the group, with strong support for non-monophyly. Colonization of the Mascarenes took place by two evolutionary distinct lineages from Madagascar, via two independent dispersal events, each unique for their spatial and temporal properties. Significant shifts in diversification rate followed regional expansion, resulting in co-occurring and phenotypically convergent species on high-elevation volcanic slopes. Like other endemic island lineages, Psiadia have been highly successful in dispersing to and radiating on isolated oceanic islands, typified by high habitat diversity and dynamic ecosystems fuelled by continued geological activity. Results stress the important biogeographical role for Rodrigues in serving as an outlying stepping stone from which regional colonization took place. We discuss how isolated volcanic islands contribute to regional diversity by generating substantial numbers of endemic species on short temporal scales. Factors pertaining to the mode and tempo of archipelago formation and its geographical isolation strongly govern evolutionary pathways available for species diversification, and the potential for successful diversification of dispersed lineages, therefore, appears highly dependent on the timing of arrival, as habitat and resource properties change dramatically over the course of oceanic island evolution.


PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.
Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington's disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.


Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice.
Scientific research highlights the central role of specific psychological processes, in particular those related to the self, in various forms of human suffering and flourishing. This view is shared by Buddhism and other contemplative and humanistic traditions, which have developed meditation practices to regulate these processes. Building on a previous paper in this journal, we propose a novel classification system that categorizes specific styles of meditation into attentional, constructive, and deconstructive families based on their primary cognitive mechanisms. We suggest that meta-awareness, perspective taking and cognitive reappraisal, and self-inquiry may be important mechanisms in specific families of meditation and that alterations in these processes may be used to target states of experiential fusion, maladaptive self-schema, and cognitive reification.


Shear Stress Estimated by Quantitative Coronary Angiography Predicts Plaques Prone to Progress and Cause Events.
This study examined the value of endothelial shear stress (ESS) estimated in 3-dimensional quantitative coronary angiography (3D-QCA) models in detecting plaques that are likely to progress and cause events. Cumulative evidence has shown that plaque characteristics and ESS derived from intravascular ultrasound (IVUS)-based reconstructions enable prediction of lesions that will cause cardiovascular events. However, the prognostic value of ESS estimated by 3D-QCA in nonflow limiting lesions is yet unclear. This study analyzed baseline virtual histology (VH)-IVUS and angiographic data from 28 lipid-rich lesions (i.e., fibroatheromas) that caused major adverse cardiovascular events or required revascularization (MACE-R) at 5-year follow-up and 119 lipid-rich plaques from a control group that remained quiescent. The segments studied by VH-IVUS at baseline were reconstructed using 3D-QCA software. In the obtained geometries, blood flow simulation was performed, and the pressure gradient across the lipid-rich plaque and the mean ESS values in 3-mm segments were estimated. The additive value of these hemodynamic indexes in predicting MACE-R beyond plaque characteristics was examined. MACE-R lesions were longer, had smaller minimum lumen area, increased plaque burden (PB), were exposed to higher ESS, and exhibited a higher pressure gradient. In multivariable analysis, PB (hazard ratio: 1.08; p = 0.004) and the maximum 3-mm ESS value (hazard ratio: 1.11; p = 0.001) were independent predictors of MACE-R. Lesions exposed to high ESS (>4.95 Pa) with a high-risk anatomy (minimal lumen area <4 mm2 and PB >70%) had a higher MACE-R rate (53.8%) than those with a low-risk anatomy exposed to high ESS (31.6%) or those exposed to low ESS who had high- (20.0%) or low-risk anatomy (7.1%; p < 0.001). In the present study, 3D-QCA-derived local hemodynamic variables provided useful prognostic information, and, in combination with lesion anatomy, enabled more accurate identification of MACE-R lesions.


Earlier multidisciplinary palliative care intervention for people with lung cancer: a systematic review and meta-analysis.
Lung cancer is the most common cancer and leading cause of cancer mortality globally. Lung cancer is associated with significant morbidity, with symptoms often being poorly managed, causing significant symptom burden for both patients and their family caregivers. In people with life-limiting illnesses including advanced cancer, palliative care has been effective in improving symptom control, physical and mental wellbeing, quality of life, and survivorship; with benefits extending to caregivers while in the role and subsequently. Earlier integration of palliative care within oncology may be associated with improved patient outcomes, and has been supported by two Lancet commissions and national guidelines. The evidence for its effectiveness, however, has been mixed across the cancer spectrum. The aim of this review was to evaluate the current evidence for the effectiveness of early integrated palliative care in improving outcomes for people with lung cancer and their caregivers. Meta-analyses were performed where studies used the same measure. Otherwise, synthesis used a narrative approach. Similar to other types of advanced cancer, this review reveals mixed evidence for the effectiveness of early referral to palliative care and for the effectiveness of individual palliative interventions for people with lung cancer and their caregivers. Evidence that on-demand palliative care is equally, if not more effective than palliative care that is routinely provided, raises the question whether initiation and provision of palliative care as part of multidisciplinary lung cancer care ought to be guided by an early referral or need-based referral. Better understanding of what constitutes palliative care when delivered to people with lung cancer and their caregivers will help delineate the correlation with reported outcomes for these populations.


Mitochondrial K+ as modulator of Ca(2+)-dependent cytotoxicity in hepatocytes. Novel application of the K(+)-sensitive dye PBFI (K(+)-binding benzofuran isophthalate) to assess free mitochondrial K+ concentrations.
In isolated rat hepatocytes a sustained high increase in intracellular free Ca2+ ([Ca2+]i), induced by extracellular ATP, is associated with mitochondrial dysfunction and cell death. The Ca(2+)-induced effects are Pi-dependent and less severe when the intracellular K+ content is low. In this study, the involvement of mitochondrial K+ processing in Ca(2+)-induced loss of mitochondrial membrane potential (MMP) and viability was investigated. The recently introduced K(+)-sensitive dye PBFI (K(+)-binding benzofuran isophthalate) has been used in combination with video-microscopy to assess intramitochondrial free K+ concentration ([K+]mito) in rat liver mitochondria in situ. After rapid permeabilization of the plasma membrane to remove cytosolic PBFI, the remaining PBFI was localized in mitochondria, and a 'resting' [K+]mito of approx. 15 mM could be measured. Increased [K+]mito levels were measured after induction of a prolonged increase in [Ca2+]i by ATP. Much lower [K+]mito, more comparable with control levels, were observed when intracellular K+ was depleted by omission of extracellular K+. In permeabilized cells the Ca(2+)-induced, Pi-dependent, dissipation of the MMP was markedly delayed in the absence of K+. These observations suggest involvement of [K+]mito as modulating agent in Ca(2+)-induced cytotoxicity in hepatocytes.


The relative merits of anabolics versus anti-resorptive compounds: where our targets should be, and whether we are addressing them.
Currently available results from fracture trials provide evidence that the most potent anti-resorptive agents reduce vertebral and non-vertebral fractures maximally by 61% and 51%, respectively. Results from the Phase III trial with denosumab, the human monoclonal antibody, are eagerly awaited. Denosumab leads to sustained 80-90% reduction of bone resorption markers, which is below the level commonly achieved with bisphosphonates, and it will be interesting to see whether this leads to an improvement in its anti-fracture efficacy over bisphosphonates. If the majority of the anti-fracture efficacy of anti-resorptive agents results from the reduction of the remodelling space (removal of stress raisers) and the conservation of structural integrity of cancellous bone, a further decrease in bone resorption might not be desirable, especially as suppression of the residual remodelling capacity could lead to an increased risk for accumulation of microdamage. In contrast to anti-resorptive agents, the bone anabolic parathyroid hormone activates modelling drifts, which act to increase trabecular thickness and add bone predominantly on the endocortical, and to a lesser degree the periosteal, surface. Despite its anabolic nature, reduction of vertebral and non-vertebral fractures is only marginally better than those achieved with anti-resorptive agents. Ageing compromises locomotor capacity and is associated with an increased risk of falls. Perhaps it is time to shift our attendance to the age-related deterioration of muscle or neuromuscular function as a target and add this 'adjuvant therapy' to the potent anti-remodelling and bone anabolic agents available for the treatment of osteoporosis if we truly want to reduce fracture incidence beyond what is possible today.


Psychosocial risk factors underlie the link between attention deficit hyperactivity symptoms and overweight at school entry.
The link between symptoms of attention deficit hyperactivity disorder (ADHD) and increased body weight is well established, while the underlying mechanisms are not yet clear. Since increased body weight and ADHD symptoms have been found to be associated with psychosocial risk factors in childhood, we analyzed whether the psychosocial risks explain the association between the two conditions. The sample consisted of 360 children (age range 6-7 years, 173 boys) attending the obligatory medical health exam before school entry. The childrens' height and weight were measured during the examination. ADHD symptoms were ascertained by parent-report questionnaires. Psychosocial risks were ascertained by a structured interview. The link between ADHD symptoms and body weight could be completely explained by cumulative psychosocial risks while controlling for gender, symptoms of depression/anxiety and oppositional defiant disorder of the child, maternal smoking during pregnancy, parental body mass index, and potential diagnosis of ADHD in the parents. In current models pertaining to the etiology of overweight/obesity and ADHD, chronic stress caused by psychosocial adversity is assumed to act as a trigger for these conditions. Psychosocial risks experienced during childhood may activate processes that specifically lead to the combined ADHD-overweight phenotype.


Immunological aspects of practolol toxicity.
It is unfortunate that there is conflicting immunological data relating to the practolol syndrome. It has not been established if "practolol patients" have some altered T cell function. The work of Behan et al. (1976) strongly supports this interpretation but other groups have not come to the same conclusion. The role of the antibody specific for a practolol metabolite needs to be determined. In practice this is going to be very difficult to do; the drug is no longer used and patients, for obvious reaons, are unwilling to take part in clinical experiments. It is likely that the nature of the metabolite will eventiually be defined and it would be a significant step forward if it could be shown that the antigenic determinant was not formed by other structurally related beta-blocking drugs. Meanwhile the stimulus to further research must be to produce an animal model system, but, for various political and economic reasons, support for such a research effort is difficult to justify.


Epitope mapping on bovine prion protein using chemical cross-linking and mass spectrometry.
An analytical strategy for the analysis of antigen epitopes by chemical cross-linking and mass spectrometry is demonstrated. The information of antigen peptides involved in the binding to an antibody can be obtained by monitoring the antigen peptides modified by a partially hydrolyzed cross-linker in the absence and in the presence of an antibody. This approach was shown to be efficient for characterization of the epitope on bovine prion protein bPrP(25-241) specifically recognized by a monoclonal antibody, 3E7 (mAb3E7), with only a small amount of sample (200 picomoles) needed. After cross-linking of the specific immuno complex, a matrix-assisted laser desorption/ionization (MALDI) mass spectrometer equipped with an ion conversion dynode (ICD) high-mass detector was used to optimize the amount of cross-linked complex formed at 202 kDa before proteolytic digestion. To identify the cross-linked peptides after proteolysis without ambiguity, isotope-labeled cross-linkers, disuccinimidyl suberate (DSS-d0/d12) and disuccinimidyl glutarate (DSG-d0/d6), together with high-resolution Fourier transform ion-cyclotron resonance mass spectrometry (FTICR-MS) were used. As a result, a complete fading of the peak intensities corresponding to the peptides representing the epitope was observed when bPrP/mAb3E7 complexes were formed.


Resistance to AHAS inhibitor herbicides: current understanding.
Acetohydroxyacid synthase (AHAS) inhibitor herbicides currently comprise the largest site-of-action group (with 54 active ingredients across five chemical groups) and have been widely used in world agriculture since they were first introduced in 1982. Resistance evolution in weeds to AHAS inhibitors has been rapid and identified in populations of many weed species. Often, evolved resistance is associated with point mutations in the target AHAS gene; however non-target-site enhanced herbicide metabolism occurs as well. Many AHAS gene resistance mutations can occur and be rapidly enriched owing to a high initial resistance gene frequency, simple and dominant genetic inheritance and lack of major fitness cost of the resistance alleles. Major advances in the elucidation of the crystal structure of the AHAS (Arabidopsis thaliana) catalytic subunit in complex with various AHAS inhibitor herbicides have greatly improved current understanding of the detailed molecular interactions between AHAS, cofactors and herbicides. Compared with target-site resistance, non-target-site resistance to AHAS inhibitor herbicides is less studied and hence less understood. In a few well-studied cases, non-target-site resistance is due to enhanced rates of herbicide metabolism (metabolic resistance), mimicking that occurring in tolerant crop species and often involving cytochrome P450 monooxygenases. However, the specific herbicide-metabolising, resistance-endowing genes are yet to be identified in resistant weed species. The current state of mechanistic understanding of AHAS inhibitor herbicide resistance is reviewed, and outstanding research issues are outlined.


See or Be? Contact with nature and well-being during COVID-19 lockdown.
This study investigated how contact with nature benefitted well-being during a strict lockdown. The study took place in Israel during the last week of the first COVID-19 lockdown, when citizens were restricted to remain within 100 m of home. A survey company distributed questionnaires among 776 individuals. The questionnaires included demographic variables (gender, ethnic and cultural groups, age, income loss due to the pandemic), contact with nature variables (Nature near home, Nature viewed from home windows, and being in nature on the preceding day), and well-being measures (positive affect, negative affect, vitality, happiness, and stress). Before completing the well-being questionnaire, participants took part in an experiment that tested the effect of viewing nature images or urban images on well-being measures. The results showed that nature near home and nature viewed from the windows contributed to higher levels of well-being, and that being in nature on the preceding day was associated with higher levels of positive affect. These benefits emerged even among those who had been economically harmed by the pandemic. Viewing nature images was also associated with level of well-being, mainly to reduced level of stress and negative affect. The current findings extend the understanding of the benefits of access to nature during stressful times, particularly during emergencies when accessing remote nature is impossible. Furthermore, the findings highlight the dual effect of contact with nature on well-being: enhancement of positive affect together with reduction of negative affect and stress. The findings indicate that exposure to nature is much more valuable for women than for men. These findings are highly important in view of gender differences in pandemic's impact on people's well-being.


Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia.
Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED.


Daily adaptive proton therapy - the key to innovative planning approaches for paranasal cancer treatments.
Background: For proton therapy of paranasal tumors, field directions avoiding volumes that might change during therapy are typically used. If the plan is optimized on the daily anatomy using daily adapted proton therapy (DAPT) however, field directions crossing the nasal cavities might be feasible. In this study, we investigated the effectiveness of DAPT for enabling narrow-field treatment approaches. Material and methods: For five paranasal tumor patients, representing a wide patient spectrum, anatomically robust 4-field-star and narrow-field plans were calculated and their robustness to anatomical and setup uncertainties was compared with and without DAPT. Based on the nominal planning CTs, per patient up to 125 simulated CTs (simCTs) with different nasal cavity fillings were created and random translations and rotations due to patient setup uncertainties were further simulated. Plans were recalculated or re-optimized on all error scenarios, representing non-adapted and DAPT fractions, respectively. From these, 100 possible treatments (60 GyRBE, 30 fx) were simulated and changes in integral dose, target and organs at risk (OARs) doses evaluated. Results: In comparison to the 4-field-star approach, the use of narrow-fields reduced integral dose between 29% and 56%. If OARs did not overlap with the target, OAR doses were also reduced. Finally, the significantly reduced target coverage in non-adapted treatments (mean V95 reductions of up to 34%) could be almost fully restored with DAPT in all cases (differences <1%). Conclusions: DAPT was found to be not only an effective way to increase plan robustness to anatomical and positional uncertainties, but also opened the possibility to use improved and more conformal field arrangements.


[Acute bilateral ophthalmoplegia and nasopharyngeal neoplasms].
The cranial nerves, due to its location, are not infrequently involved in the nasopharyngeal neoplasm evolutionary course. In this paper we describe two cases in which the neoplastic infiltration in both cavernous sinuses brought the appearance of an acute bilateral ophthalmolegia on. This symptomatology meant, in the first case, the onset of disease. In the second one, it was the reason of consultation. Later we discuss the topographic location of the damages in both cavernous sinuses considering the observed neurological shortcomings. Finally we approach a short revision of the causes of bilateral ophthalmoplegia found in literature, as well as an evaluation of different radiological diagnosis methods for this kind of damages.


Reciprocity failure in continuous-wave holography.
Reciprocity failure is shown to occur at beam irradiances commonly obtainable in continuous-wave holography with an argon-ion laser. Results are given for a variety of common developers used with Agfa-Gevaert material, and typical graphs of optical density versus exposure time at nominally constant exposure levels are shown. A variation in optical density of up to 50% is seen to occur between 0.125-s and 8-s exposure times for constant irradiance-time products. The conclusion is drawn that, when used as described, faster developers exhibit greater reciprocity failure than slower developers.


Long-term radiographic follow-up of total hip replacements.
This report relates the long-term clinical result with the serial radiologic findings of 350 consecutive total hip replacements done by the author. Thirteen femoral components and one acetabular component have been revised, and 12 of the 14 components had shown radiologic changes in the surrounding cement prior to the need for revision. Available roentgenograms at 6 weeks, 1 year, 5 years, and 8 to 10 years after surgery made radiologic assessment possible in 129 hips. Heterotopic bone formation, calcar resorption and distal cortical hypertrophy all appeared to be primarily radiologic findings with little effect on clinical results. A variety of changes seen in the cement or bone-cement interface were noted on the femoral component side of 13.6% of the hips. None of these patients had any symptoms or functional limitations. These radiologic femoral cement mantle changes showed a high correlation with apparently inadequate initial cementing techniques and were usually already seen on the 1- and 5-year postoperative roentgenogram. Only one acetabular cup was identified as radiologically loose and one as migrated. Radiolucent lines at the bone-cement interface on the acetabular side showed vascillating increases and decreases on the serial roentgenograms. Since the lucent lines on the acetabular component side improved as often as they increased in size, these lucencies did not seem to be of similar predictive value as those on the femoral side. Of the hips followed 8 to 10 years only 2 circumferential and 10 lucencies greater than 2 mm could be found. I could not correlate these with inadequate cup position or inadequate cement mantle on the initial radiograph. The 29 patients in this series who were under 50 years of age did not have a revision rate or radiologic change different from the group as a whole.