Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells.
Smooth muscle cell proliferation is a key event in the development of intimal hyperplasia after arterial injury. Heparin can suppress smooth muscle cell proliferation in vitro and prevents intimal hyperplasia after arterial injury, but the mechanisms of action are poorly understood. Recently, we observed that heparin inhibited serum-induced activation of mitogen-activated protein kinase in smooth muscle cells, but heparin did not inhibit signaling induced by platelet-derived growth factor BB and basic fibroblast growth factor, both ligands of tyrosine kinase receptors. Here, we examined the possibility that heparin inhibits signaling by thrombin and other activators of heterotrimeric G-proteins. Baboon aortic smooth muscle cells were stimulated with thrombin, angiotensin II, endothelin-1, and lysophosphatidic acid in the presence or absence of heparin. After stimulation, mitogen-activated protein kinase activity was measured with an in-gel phosphorylation assay, mitogen-activated protein kinase kinase-1 was immunoprecipitated from the same samples, and activity was measured with recombinant mitogen-activated protein kinase as a substrate. DNA synthesis was measured by 3H-thymidine labeling and scintillation counting. Heparin inhibited sustained activity of mitogen-activated protein kinase kinase-1 and mitogen-activated protein kinase and prevented DNA synthesis induced by thrombin, angiotensin II, endothelin-1, and lysophosphatidic acid. Heparin inhibits growth of baboon smooth muscle cells by preventing prolonged mitogen-activated protein kinase activation elicited by ligands of seven transmembrane domain receptors and heterotrimeric G-proteins. The results indicate that heparin interferes with a specific pathway in smooth muscle cell growth, which could be a future target in attempts to inhibit lesion development after vascular surgery.


Can NKT cells extinguish smoldering myeloma?
One of the greatest challenges in all of medicine is to improve on the life of an asymptomatic patient; however, in this issue of Blood, Richter and colleagues share provocative new data taking steps toward accomplishing this goal.


The role of beta-catenin signaling in the malignant potential of cystitis glandularis.
Chronic inflammation is a risk factor for malignant transformation in the bladder. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) is a mediator of such inflammation that induces nuclear localization of the adherens junction component beta-catenin. This mechanism has a key role in the initiation and progression of the premalignant lesion Barrett's metaplasia of the esophagus. Cystitis glandularis is a metaplastic lesion of the bladder urothelium occurring in the presence of chronic inflammation and in up to 13% of asymptomatic bladders. Two subtypes are described (typical and intestinal/colonic) with uncertain malignant potential. Etiologically and histologically cystitis glandularis mimics Barrett's metaplasia. We investigated the roles of beta-catenin and TNFalpha in cystitis glandularis. Immunohistochemistry and immunofluorescence were used to demonstrate the expression and localization of E-cadherin, beta-catenin and TNFalpha in 9 sections of typical cystitis glandularis and 4 of intestinal/colonic cystitis glandularis. Appropriate controls were used for all experiments. Immunohistochemistry demonstrated normal membranous expression of E-cadherin and beta-catenin in all cystitis glandularis sections with increased TNFalpha expression. Immunofluorescence showed nuclear localization of beta-catenin in the intestinal/colonic subtype only, which was not observed in typical cystitis glandularis. The presence of nuclear beta-catenin suggests that intestinal/colonic cystitis glandularis shares the same signaling pathway with the premalignant lesion Barrett's metaplasia of the esophagus and the intestinal/colonic subtype of cystitis glandularis may have the potential to progress to malignancy. This finding has important implications for the management of this lesion.


Protein-specific glycosyltransferases: how and why they do it!
Glycosylation is a common and complex form of post-translational protein modification. Although a large and increasing number of unique structures is known to exist, most arise from a series of common synthetic intermediates and differ at their periphery. Glycosyltransferases, which recognize both the oligosaccharide acceptor and features of the underlying protein, may account for the synthesis of many unique oligosaccharides, particularly those associated with biologic functions dependent on specific oligosaccharide structures. UDP-Glc: glycoprotein glucosyltransferase, UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, and UDP-GalNAc:glycoprotein hormone N-acetylgalactosaminyltransferase are examples of glycosyltransferases that display peptide specificity. The features of peptide recognition are distinct for these three transferases and provide insights into the range of properties that can be expected for such transferases. Peptide-specific glycosyltransferases promise new insights into the regulation of glycosylation and its numerous biologic functions. They will also ultimately provide tools for engineering glycoproteins bearing specific oligosaccharide structures.


Fuzzy clustering analysis of microarray data.
Fuzzy clustering is a useful tool for identifying relevant subsets of microarray data. This paper proposes a fuzzy clustering method for microarray data analysis. An advantage of the method is that it used a combination of the fuzzy c-means and the principal component analysis to identify the groups of genes that show similar expression patterns. It allows a gene to belong to more than a gene expression pattern with different membership grades. The method is suitable for the analysis of large amounts of noisy microarray data.


Research Progress Regarding Interfacial Characteristics and the Strengthening Mechanisms of Titanium Alloy/Hydroxyapatite Composites.
Titanium alloy/Hydroxyapatite (HA) composites have become a hot research topic in biomedical materials, while there are some challenges concerning bioactivity and mechanical properties such as low interface adhesion at the interface between metal and ceramic, complex interfacial reactions, and so on. Nevertheless, composites with reinforced phases can reach special properties that meet the requirements of biomedical materials due to the strong interfacial interactions between reinforcing phases (nano-carbon, partial oxides, and so on) and Titanium alloys or HA. This review summarizes the interface properties and mechanisms of Titanium alloy/HA composites, including interfacial bonding methods, strengthening and toughening mechanisms, and performance evaluation. On this basis, the interface characteristics and mechanisms of the Titaniumalloy/HA composites with enhanced phase are prospected. The results show that the interfacial bonding methods in the Titanium alloy/HA composites include chemical reactions and mechanical effects. The strengthening and toughening mechanisms contain grain refinement strengthening, second phase strengthening, solution strengthening, cracks and pulling out mechanisms, etc. This review provides a guidline for the fabrication of biocomposites with both mechanical properties and bioactivity.


Molecular chirality in meteorites and interstellar ices, and the chirality experiment on board the ESA cometary Rosetta mission.
Life, as it is known to us, uses exclusively L-amino acid and D-sugar enantiomers for the molecular architecture of proteins and nucleic acids. This Minireview explores current models of the original symmetry-breaking influence that led to the exogenic delivery to Earth of prebiotic molecules with a slight enantiomeric excess. We provide a short overview of enantiomeric enhancements detected in bodies of extraterrestrial origin, such as meteorites, and interstellar ices simulated in the laboratory. Data are interpreted from different points of view, namely, photochirogenesis, parity violation in the weak nuclear interaction, and enantioenrichment through phase transitions. Photochemically induced enantiomeric imbalances are discussed more specifically in the topical context of the "chirality module" on board the cometary Rosetta spacecraft of the ESA. This device will perform the first enantioselective in situ analyses of samples taken from a cometary nucleus.


Pain experienced by patients during periodontal maintenance treatment.
The aims of this study were to assess the degree of pain experienced by patients during probing and debridement and to determine whether the pain responses could be predicted by the patient's age, gender, percentage of sites > or = 4 mm deep, and responses to a questionnaire on dental anxiety. Prior to the maintenance procedures, 26 adult patients completed an anxiety questionnaire. Subsequently, measurements of probing depths were performed. The patients activated a tallying device at each probe entry that evoked pain (pain frequency). Pain levels for each quadrant were also assessed with a visual analog scale (VAS). Following probing, the same protocol was repeated during instrumentation (debridement). Most patients showed low pain responses to both probing and instrumentation as evaluated by both methods of measurement. However, using arbitrary thresholds of pain frequency > or = 50% and VAS > or = 40 mm, approximately 15% of the patients had a painful experience. Stepwise multiple regression analyses disclosed that significant portions of the pain levels could be predicted by gender and the patients' answers to 2 of the dental anxiety questions. Recognition of patients who are likely to experience pain during periodontal treatment can be facilitated by the use of 2 questions on dental anxiety and the VAS response to probing during examination.


Ten-years trend of dengue research in Indonesia and South-east Asian countries: a bibliometric analysis.
Dengue fever is a mosquito-borne viral disease with high incidence in over 128 countries. WHO estimates 500,000 people with severe dengue are hospitalized annually and 2.5% of those affected die. Indonesia is a hyperendemic country for dengue with an increasing number of cases in the last decade. Unfortunately, the trends of Indonesian dengue research are relatively unknown. This research aimed to depict bibliographic trends and knowledge structure of dengue publications in Indonesia relative to that of South-east Asia (SEA) from 2007 to 2016. Bibliographic data were collected from PubMed filtered by Indonesia country affiliation. The annual growth rate of publication was measured and compared with neighborhood countries in the SEA region. Network analysis was used to visualize emerging research issues. About 1,625 dengue-related documents originated from SEA region, of which Indonesia contributed 5.90%. The publication growth rate in Indonesia, however, is the highest in ASEAN region (28.87%). Total citations for documents published from Indonesia was 980, with an average of 14 citations per publication and h-index of 16. Within the first five years, the main research topics were related to insect vector and diagnostic method. While insect vector remained dominant in the last five years, other topics such as disease outbreak, dengue virus, and dengue vaccine started emerging. In the last 10 years, dengue publications' growth from Indonesia in international journals improved significantly, despite less number of publications compared to other SEA countries. Efforts should be made to improve the quantity and quality of publications from Indonesia. The research topics related to dengue in Indonesia are in line with studies in SEA. Stakeholders and policy makers are encouraged to develop a roadmap for dengue research in the future.


Aortic Aging in ESRD: Structural, Hemodynamic, and Mortality Implications.
Aging incurs aortic stiffening and dilation, but these changes are less pronounced in peripheral arteries, resulting in stiffness and geometry gradients influencing progression of the forward and reflected pressure waves. Because premature arterial aging is observed in ESRD, we determined the respective roles of stiffness and aortic geometry gradients in 73 controls and 156 patients on hemodialysis. We measured aortic pulse wave velocity (PWV) and brachial PWV to evaluate the stiffness gradient [(brachial PWV/aortic PWV)(0.5)] and ascending aortic and aortic bifurcation diameters to assess aortic taper (ascending aortic diameter/aortic bifurcation diameter). The global reflection coefficient was estimated from characteristic impedance and vascular resistance. Cox proportional hazard models were used to determine mortality risk. The age-associated increase in aortic PWV was higher in patients (P<0.001). In controls, aortic ascending and bifurcation diameters increased with age, with an unchanged aortic taper. In patients on hemodialysis, age did not associate with increased ascending aortic diameter but did associate with increased aortic bifurcation diameter and decreased aortic taper, both of which also associated with abdominal aortic calcifications and smaller global reflection coefficient (P<0.001). In patients, multivariate models revealed all-cause and cardiovascular mortality associated with age, aortic PWV, and aortic bifurcation diameter with high specificity and sensitivity. Using stiffness gradient, aortic taper, or global reflection coefficient in the model produced similar results. Thus, whereas aortic stiffness is a known independent predictor of mortality, these results indicate the importance of also evaluating the aortic geometry in patients on hemodialysis.


Effects of head blow on the development of hearing loss.
The effects of the direction and intensity of the head blow and the effects of the lapse of time after a head blow on the development of hearing loss were studied in guinea pigs. The electrical responses from the right inferior colliculus (ER) and from the left round window (CP) to acoustic stimuli were measured. The elevation in threshold of the ER in the presence of normal CP in guinea pigs after a head blow suggests that the site of the lesion is central to the cochlea.


Pyoderma gangrenosum associated with transient acantholytic dermatosis (pemphigus erythematosus-like) and paraproteinemia.
A 69-year-old man with recurrent eruptions of pyoderma gangrenosum for 4 years is described. The patient also suffered from paraproteinemia (increased IgA with M-component) and transient acantholytic dermatosis resembling pemphigus erythematosus. He had no intestinal symptoms.


Immunohistochemical localization of steroidogenic enzymes and prolactin receptors in the corpus luteum and placenta of spotted seals (Phoca largha) during late pregnancy.
To study luteal function in the late gestational period of Phocidae (seals), we analyzed the localization of steroidogenic enzymes (P450scc, 3betaHSD and P450arom) and prolactin receptors in the corpora lutea of pregnant spotted seals (Larga seal; Phoca largha) immunohistochemically. P450scc, 3betaHSD and prolactin receptors were present in all luteal cells of each corpus luteum, and most luteal cells were immunostained for P450arom. Although we analyzed only two specimens, P450scc, 3betaHSD and prolactin receptors were negatively immunostained in the placentae. P450arom was present in the syncytiotrophoblast of placentae. These findings suggest that 1) the corpus luteum of the spotted seal synthesizes pregnenolone, progesterone and estrogen during late gestational period, 2) the placenta of this species do not possess the capacity to synthesize progesterone, and 3) like other terrestrial carnivores, this species requires prolactin to maintain the corpus luteum during pregnancy. These characteristics support the recent classification of family Phocidae in the order Carnivora, and suggest a relationship between prolactin and reproductive failure during the post-implantation period in pinnipeds.


The Effects of Epidermal Neural Crest Stem Cells on Local Inflammation Microenvironment in the Defected Sciatic Nerve of Rats.
Cell-based therapy is a promising strategy for the repair of peripheral nerve injuries (PNIs). epidermal neural crest stems cells (EPI-NCSCs) are thought to be important donor cells for repairing PNI in different animal models. Following PNI, inflammatory response is important to regulate the repair process. However, the effects of EPI-NCSCs on regulation of local inflammation microenviroment have not been investigated extensively. In the present study, these effects were studied by using 10 mm defected sciatic nerve, which was bridged with 15 mm artificial nerve composed of EPI-NCSCs, extracellular matrix (ECM) and poly (lactide-co-glycolide) (PLGA). Then the expression of pro- and anti-inflammatory cytokines, polarization of macrophages, regulation of fibroblasts and shwann cells (SCs) were assessed by western blot, immunohistochemistry, immunofluorescence staining at 1, 3, 7 and 21 days after bridging. The structure and the function of the bridged nerve were determined by observation under light microscope and by examination of right lateral foot retraction time (LFRT), sciatic function index (SFI), gastrocnemius wet weight and electrophysiology at 9 weeks. After bridging with EPI-NCSCs, the expression of anti-inflammatory cytokines (IL-4 and IL-13) was increased, but decreased for pro-inflammatory cytokines (IL-6 and TNF-α) compared to the control bridging, which was consistent with increase of M2 macrophages and decrease of M1 macrophages at 7 days after transplantation. Likewise, myelin-formed SCs were significantly increased, but decreased for the activated fibroblasts in their number at 21 days. The recovery of structure and function of nerve bridged with EPI-NCSCs was significantly superior to that of DMEM. These results indicated that EPI-NCSCs could be able to regulate and provide more suitable inflammation microenvironment for the repair of defected sciatic nerve.


Metabotropic glutamate receptors: potential drug targets for psychiatric disorders.
Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.


[The influence of medical standards, medical guidelines and economic restrictions on the standard of legal liability].
First we will have to identify the components determining the standard for medical liability in civil law cases. The civil courts have so far uniformly regarded the medical standard defined by physicians themselves as the standard of legal liability. Medical standards are based on scientific knowledge, practical experience and professional acceptance. Clinical guidelines can but need not necessarily reflect medical standards. Moreover, they cannot establish a standard. Second, on this basis the question will be whether economic restrictions should be allowed to alter the standard of legal liability. The answer depends, namely on what is meant by economic restrictions--rationalising or rationing? Rationalising need not be inconsistent with the standard. There are contradicting opinions in the legal literature about whether rationing is considered permissible. With regard to our social insurance system some authors point out that the highest possible standard is established by the statutory health insurance. With reference to the civil law, though, others demand that the medical standard must be given top priority. In accordance with the latter opinion rationing is only permitted in cases of a natural shortage of resources. Shortage of economic resources must not influence the standard of legal liability.


Pathophysiology of Huntington's disease: from huntingtin functions to potential treatments.
Drugs used to treat Huntington's disease act on the symptoms but do not slow the disease process itself. This review focuses on recent pathogenetic findings and on emerging therapeutic approaches. Basic research is providing novel insights into the complex molecular pathways involved in the pathogenesis of Huntington's disease. Several mechanisms have been identified that mediate neuronal dysfunction and death; these include neuronal aggregation of the mutated protein, transcriptional dysregulation, excitotoxicity, altered energy metabolism, impaired axonal transport, and altered synaptic transmission. Recent experimental works have identified potential new therapeutic targets. In particular, they emphasize the role of altered histone modifications in transcriptional dysregulation, the synergistic action of glutamatergic and dopaminergic pathways in inducing excitotoxicity, the neuroprotective effect of brain-derived neurotrophic factor expression and transport restoration, and the possibility of reducing the expression of the mutant protein huntingtin and its deleterious effects by using short interfering mRNAs. Successful neuroprotective therapy for Huntington's disease patients is likely to involve a combined approach targeting both cellular and molecular mediators that account for the toxicity of mutated huntingtin.


Relationships between ambulance transports for alcohol intoxication and assault.
To evaluate the association between ambulance transports for assault and those for alcohol intoxication. A retrospective analysis of emergency medical services (EMS) calls was performed. The authors used logistic regression models to compare patients transported for alcohol intoxication with a control group of patients transported for respiratory distress (asthma or shortness of breath) with respect to whether they had been transported on a separate occasion for a chief complaint of assault. Patients transported for alcohol intoxication had 9 times the risk of transport for assault as compared with the control group (OR = 9.3; 95% CI = 6.4, 13.6). The odds of transport for assault among the alcohol patients increased 17.1% with each alcohol transport (OR = 1.17; 95% CI = 1.14, 1.20) but decreased for the control group (OR = 0.34; 95% CI = 0.26, 0.44). Repeat transports for assault were more common among the alcohol patients than among the control group (OR = 3.3; 95% CI = 1.1, 11.3). The mean number of assault transports was higher among the alcohol patients than among the patients never transported for alcohol intoxication (p < 0.0001). Patients transported on multiple occasions for acute alcohol intoxication are at relatively high risk for assault. This risk group should be targeted for focused assault prevention interventions that include components designed to reduce incidents of repeat alcohol intoxication.


Treatment of children with perennial rhinitis with brompheniraminemaleate and phenylpropanolaminehydrochloride (lunerin mite)
The effect of a combined pediatric preparation of brompheniramine maleate and phenylpropanolaminehydrochloride (Lunerin mite) was studied in 17 children (aged 4-14 years) with allergic rhinitis. A double-blind cross-over technique was used, and a score system was used for evaluation of symptoms and signs. The results show that the drug had a good effect with statistical differences on the 1 per cent level between the active preparation and the placebo. The effect was less pronounced in children aged more than 10 years, for whom a higher dose of the drug is recommended. The frequency of side-effects was negligible.


Dynamic Kinetic Resolution in Rhodium-Catalyzed Asymmetric Arylation of Phospholene Oxides.
The reaction of 2,5-dihydro-1H-phosphole 1-oxide 1 with ArB(pin) 3 in the presence of a chiral (R)-segphos-rhodium catalyst under highly basic conditions (10 equiv of KOH) gave high yields of (1S,3S)-3-arylphospholane 1-oxide 4 with high diastereoselectivity as well as high enantioselectivity. Equilibration of 1 with its 2,3-dihydro isomer 2, which is chiral and racemic, by base-catalyzed olefin isomerization followed by kinetic resolution of 2 with the chiral rhodium catalyst realized the present dynamic kinetic resolution.


Effect of short-term air storage after removal from controlled-atmosphere storage on apple and fresh-cut apple quality.
One of the realities of apple distribution for long-term stored fruit is that a controlled-atmosphere (CA) storage room will be unsealed and fruit held in air storage and marketed over several weeks. This work was conducted to determine the effect of post-CA air storage of whole fruit on potential shelf life for fresh-cut apple slices. Fresh-cut slices of 'Spartan' and 'Delicious' apples held in post-CA air storage for 2 or 4 weeks showed the least changes in cut surface color as compared with those made from apples immediately on removal from CA. Shelf life was most improved by post-CA air storage in the 'Spartan' apples, which were more advanced in maturity as compared with the 'Delicious' apples. Internal ethylene concentration, firmness, and respiration changed significantly with post-CA air storage, suggesting a relationship between physiological status of the whole fruit and shelf life of slices made from that fruit. The results support the hypothesis that apples had suppressed physiological activity in CA storage and are susceptible to accelerated deterioration upon cutting. Holding fruit for 2 weeks in air storage allowed recovery of physiological activity, which resulted in greater resistance to deterioration in response to fresh-cut processing.


[Relapse of Hodgkin lymphoma: second and subsequent line treatments].
2ND AND SUBSEQUENT LINE TREATMENTS. Patients who fail first-line treatment can be cured with salvage chemotherapy followed by intensified therapy and hematopoietic stem cell autotransplantation. This treatment strategy is feasible for patients who are eligible based on their age, with chemosensitive disease and associated comorbidities. There is no standard of care for salvage chemotherapy, but patients who are in complete remission prior to transplantation have the best prognosis. Combinations of salvage therapy, including new molecules, have shown interesting results, but without comparative trials. The use of brentuximab vedotin as a maintenance treatment post autotransplant has been evaluated for patients at high risk of relapse, resulting in a significant improvement in progression-free survival. Allograft is a curative option for postautotransplant relapse; however, immunotherapy with antiPD1 calls into question the role and timing of allograft.


Developing a privacy-preserving deep learning model for glaucoma detection: a multicentre study with federated learning.
Deep learning (DL) is promising to detect glaucoma. However, patients' privacy and data security are major concerns when pooling all data for model development. We developed a privacy-preserving DL model using the federated learning (FL) paradigm to detect glaucoma from optical coherence tomography (OCT) images. This is a multicentre study. The FL paradigm consisted of a 'central server' and seven eye centres in Hong Kong, the USA and Singapore. Each centre first trained a model locally with its own OCT optic disc volumetric dataset and then uploaded its model parameters to the central server. The central server used FedProx algorithm to aggregate all centres' model parameters. Subsequently, the aggregated parameters are redistributed to each centre for its local model optimisation. We experimented with three three-dimensional (3D) networks to evaluate the stabilities of the FL paradigm. Lastly, we tested the FL model on two prospectively collected unseen datasets. We used 9326 volumetric OCT scans from 2785 subjects. The FL model performed consistently well with different networks in 7 centres (accuracies 78.3%-98.5%, 75.9%-97.0%, and 78.3%-97.5%, respectively) and stably in the 2 unseen datasets (accuracies 84.8%-87.7%, 81.3%-84.8%, and 86.0%-87.8%, respectively). The FL model achieved non-inferior performance in classifying glaucoma compared with the traditional model and significantly outperformed the individual models. The 3D FL model could leverage all the datasets and achieve generalisable performance, without data exchange across centres. This study demonstrated an OCT-based FL paradigm for glaucoma identification with ensured patient privacy and data security, charting another course toward the real-world transition of artificial intelligence in ophthalmology.


Highly excited electronic image states of metallic nanorings.
We study electronic image states around a metallic nanoring and show that the interplay between the attractive polarization force and a repulsive centrifugal force gives rise to Rydberg-like image states trapped several nanometers away from the surface. The nanoring is modeled as a perfectly conducting isolated torus whose classical electrostatic image potential is derived analytically. The image states are computed via a two-dimensional finite-difference scheme as solutions of the effective Schrödinger equation describing the outer electron subject to this image potential. These findings demonstrate not only the existence of detached image states around nanorings but allow us also to provide general criteria on the ring geometry, i.e., the aspect ratio of the torus, that need to be fulfilled in order to support such states.


Apoptosis of wound fibroblasts induced by oxidative stress.
Irreversible lung parenchymal injury is usually healed by fibrosis, which depends on the abilities of fibroblasts to proliferate, migrate into the wound, and survive. Because the lung is frequently exposed to increased oxidative stress, which is thought to mediate apoptosis, we examined whether oxidative stress induces apoptosis in fibroblasts during wound healing. We performed an in vitro scratch wound assay where cultured fibroblast monolayers were exposed to H2O2 (10-500 microM) after artificial wounding. Apoptosis was evaluated by nuclear staining with Hoechst33342 or terminal deoxynucleotidyl transferase (TdT)-mediated nucleotide nick end-labeling (TUNEL). Intracellular oxidants were assessed with the peroxide-sensitive fluorochrome carboxydichlorodihydrofluorescein (CDCF). We found that repopulating fibroblasts at the wound margin, but not quiescent fibroblasts at the intact site, selectively underwent oxidant accumulation and apoptosis in response to H2O2 exposure. Some of the apoptotic cells had incorporated bromodeoxyuridine (BrdU), an indicator of proliferating cells. These results suggest that oxidative stress selectively induces apoptosis in fibroblasts that are stimulated to proliferate and/or migrate into the wound. Fibroblast apoptosis induced by oxidative stress during wound repopulation may be relevant to intractable wound healing.


Two novel mitogen-activated protein signaling components, OsMEK1 and OsMAP1, are involved in a moderate low-temperature signaling pathway in rice.
Rice (Oryza sativa) anther development is easily damaged by moderately low temperatures above 12 degrees C. Subtractive screening of cDNA that accumulated in 12 degrees C-treated anthers identified a cDNA clone, OsMEK1, encoding a protein with features characteristic of a mitogen-activated protein (MAP) kinase kinase. The putative OsMEK1 protein shows 92% identity to the maize (Zea mays) MEK homolog, ZmMEK1. OsMEK1 transcript levels were induced in rice anthers by 12 degrees C treatment for 48 h. Similar OsMEK1 induction was observed in shoots and roots of seedlings that were treated at 12 degrees C for up to 24 h. It is interesting that no induction of OsMEK1 transcripts was observed in 4 degrees C-treated seedlings. In contrast, rice lip19, encoding a bZIP protein possibly involved in low temperature signal transduction, was not induced by 12 degrees C treatment but was induced by 4 degrees C treatment. Among the three MAP kinase homologs cloned, only OsMAP1 displayed similar 12 degrees C-specific induction pattern as OsMEK1. A yeast two-hybrid system revealed that OsMEK1 interacts with OsMAP1, but not with OsMAP2 and OsMAP3, suggesting that OsMEK1 and OsMAP1 probably function in the same signaling pathway. An in-gel assay of protein kinase activity revealed that a protein kinase (approximately 43 kD), which preferentially uses myelin basic protein as a substrate, was activated by 12 degrees C treatment but not by 4 degrees C treatment. Taken together, these results lead us to conclude that at least two signaling pathways for low temperature stress exist in rice, and that a MAP kinase pathway with OsMEK1 and OsMAP1 components is possibly involved in the signaling for the higher range low-temperature stress.


Molecular Koch's postulates applied to microbial pathogenicity.
Microbial genetics and molecular cloning now permit us to routinely isolate specific genes from a variety of microbial pathogens. Obviously not all genes from pathogenic microorganisms play a role in pathogenicity or virulence. Just as Koch's postulates were formulated to identify the causal relationship between an organism and a specific disease, the notion is presented here that a form of molecular Koch's postulates is needed when examining the potential role of genes and their products in the pathogenesis of infection and disease.


Novel reactivity mode of hydroxamic acids: a metalla-pinner reaction.
The reaction between the nitrile complex trans-[PtCl(4)(EtCN)(2)] and benzohydroxamic acids RC(6)H(4)C([double bond]O)NHOH (R = p-MeO, p-Me, H, p-Cl, o-HO) proceeds smoothly in CH(2)Cl(2) at approximately 45 degrees C for 2-3 h (sealed tube) or under focused 300 W microwave irradiation for approximately 15 min at 50 degrees C giving, after workup, good yields of the imino complexes [PtCl(4)[NH[double bond]C(Et)ON[double bond]C(OH)(C(6)H(4)R)](2)] which derived from a novel metalla-Pinner reaction. The complexes [PtCl(4)[NH[double bond]C(Et)ON[double bond]C(OH)(C(6)H(4)R)](2)] were characterized by elemental analyses (C, H, N), FAB mass spectrometry, and IR and (1)H and (13)C[(1)H] spectroscopies, and [PtCl(4)[NH[double bond]C(Et)ON[double bond]C(OH)(Ph)](2)] (as the bis-dimethyl sulfoxide solvate), by X-ray single-crystal diffraction. The latter disclosed its overall trans-configuration with the iminoacyl species in the hydroximic tautomeric form in E-configuration which is held by N[bond]H...N hydrogen bond between the imine [double bond]NH atom and the hydroximic N atom.


Heart diseases following radiotherapy.
Three women had cardiac complaints 10-17 years after a radical mastectomy and radiotherapy for cancer of the left breast. Their ages were 42, 43 and 57 years, respectively. The first patient had a precocious coronary artery disease (CAD). She had segmental stenosis in the middle and distal portions of the left main coronary artery and pericardial fibrosis. Symptoms and signs of severe pericardial constriction became the problem after bypass surgery. She died 1 year later due to cardiorespiratory failure. The second case had sick sinus syndrome presenting a prolonged pause for 12 seconds alternating with tachy- and bradyarrhythmias, a complete atrio-ventricular block in association with pericardial effusion plus aortic and mitral valvular regurgitation. The condition improved after the implantation of a permanent pacemaker. To date, this is a very rare complication of radiation induced panconduction disturbance. The third patient had significant stenosis in the proximal portion of the left anterior descending coronary artery and myocardial fibrosis was proven by an endocardial biopsy. She had an uneventful course after medical treatment.


Use of orlistat (xenical) to treat chylous ascites.
Chylous ascites is uncommon and occurs in about 1 in 20,000 hospital admissions. Causes include disruption of the lymphatic system due to malignancy, cirrhosis, surgery, or radiation therapy. The mainstay of therapy has been low-fat diet supplemented with medium-chain triglyceride oil. However, dietary compliance can be difficult to achieve for adequate response. We report a 47-year-old man with hepatitis C and alcohol-related cirrhosis with new-onset chylous ascites and chylothorax. His ascites triglyceride was 585 mg/dL, and the pleural fluid triglyceride was 691 mg/dL. Ascitic and pleural fluid cytology and acid-fast bacilli stain were negative. The patient was treated with low-fat diet and medium-chain triglyceride oil. However, his ascites remained chylous after 1 week of treatment because of poor compliance with the dietary restrictions. Orlistat was then added to his treatment regimen. A half week later, the chylous component of his ascites resolved. Remaining high-volume clear ascites was treated with placement of a transjugular intrahepatic portosystemic shunt. To our knowledge, orlistat has never been used in the treatment of chylous ascites. This case suggests the potential value of adding orlistat to low-fat diet and medium-chain triglyceride oil in the treatment of chylous ascites, especially in patients who are unable to comply with the dietary restrictions.


Cdc2/cyclin B1 interacts with and modulates inositol 1,4,5-trisphosphate receptor (type 1) functions.
The resistance of inositol 1,4,5-trisphosphate receptor (IP3R)-deficient cells to multiple forms of apoptosis demonstrates the importance of IP3-gated calcium (Ca2+) release to cellular apoptosis. However, the specific upstream biochemical events leading to IP3-gated Ca2+ release during apoptosis induction are not known. We have shown previously that the cyclin-dependent kinase 1/cyclin B (cdk1/CyB or cdc2/CyB) complex phosphorylates IP3R1 in vitro and in vivo at Ser421 and Thr799. In this study, we show that: 1) the cdc2/CyB complex directly interacts with IP3R1 through Arg391, Arg441, and Arg871; 2) IP3R1 phosphorylation at Thr799 by the cdc2/CyB complex increases IP3 binding; and 3) cdc2/CyB phosphorylation increases IP3-gated Ca2+ release. Taken together, these results demonstrate that cdc2/CyB phosphorylation positively regulates IP3-gated Ca2+ signaling. In addition, identification of a CyB docking site(s) on IP3R1 demonstrates, for the first time, a direct interaction between a cell cycle component and an intracellular calcium release channel. Blocking this phosphorylation event with a specific peptide inhibitor(s) may constitute a new therapy for the treatment of several human immune disorders.


Accuracy of linear measurements around dental implants by means of cone beam computed tomography with different exposure parameters.
The aim of this study was to determine the accuracy of linear measurements around dental implants when using CBCT unit devices presenting different exposure parameters. Dental implants (n = 18) were installed in the maxilla of human dry skulls, and images were obtained using two CBCT devices: G1-Care Stream 9300 (70 kVp, 6.3 mA, voxel size 0.18 mm, field of view 8 × 8 cm; Carestream Health, Rochester, NY) and G2-R100 Veraview® (75 kVp, 7.0 mA, voxel size 0.125 mm, field of view 8 × 8 cm; J Morita, Irvine, CA). Measurements of bone thickness were performed at three points located (A) in the most apical portion of the implant, (B) 5 mm above the apical point and (C) in the implant platform. Afterwards, values were compared with real measurements obtained by an optical microscopy [control group (CG)]. Data were statistically analyzed with the significance level of p ≤ 0.05. There was no statistical difference for the mean values of bone thickness on Point A (CG: 4.85 ± 2.25 mm, G1: 4.19 ± 1.68 mm, G2: 4.15 ± 1.75 mm), Point B (CG: 1.50 ± 0.84 mm, G1: 1.61 ± 1.27 mm; G2: 1.68 ± 0.82 mm) and Point C (CG: 1.78 ± 1.33 mm, G1: 1.80 ± 1.09 mm; G2: 1.64 ± 1.11 mm). G1 and G2 differed in bone thickness by approximately 0.76 mm for Point A, 0.36 mm for Point B and 0.08 mm for Point C. A lower intraclass variability was identified for CG (Point A = 0.20 ± 0.25; Point B = 0.15 ± 0.20; Point C = 0.06 ± 0.05 mm) in comparison with G1 (Point A = 0.56 ± 0.52; Point B = 0.48 ± 0.50; Point C = 0.47 ± 0.56 mm) and G2 (Point A = 0.57 ± 0.51; Point B = 0.46 ± 0.46; Point C = 0.36 ± 0.31 mm). CBCT devices showed acceptable accuracy for linear measurements around dental implants, despite the exposure parameters used.


Control of the innate immune response by the mevalonate pathway.
Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.


Exergames as Coping Strategies for Anxiety Disorders During the COVID-19 Quarantine Period.
The COVID-19 outbreak has led to wide-scale self-isolation, as a result of the quarantine period recommended by the World Health Organization. Consequently, people's mental health, including their anxiety levels, may be becoming impaired. To cope with the situation, the exergame appears to be an enjoyable easy-to-use tool for reducing social isolation, as well as an interesting mode of home-based exercise for tackling anxiety disorders and sedentary behavior. This article critically appraises the opportunities and challenges exergames present for the prevention and treatment of anxiety disorders in a home-based environment during the COVID-19 quarantine period.


Partial homology of stress glycoprotein GP62 with HSP70.
Thermotolerance and heat resistance are often associated with elevated levels of heat shock proteins (HSPs) and a selective increase in protein glycosylation. In the present study, we have characterized heat stress-induced protein glycosylation in M21 cells, derived from the rat fibroblast line, Rat-1. M21 cells are characterized by constitutive overexpression of human HSP70 gene and show increased heat resistance without loss of its normal capacity for thermotolerance development after heat conditioning (Li et al., 1991, Proc. Natl. Acad. Sci. USA 88, 1681-1685). The data presented here show that the elevated heat resistance in these cells is associated not only with the constitutive overexpression of human HSP70, but also with increased glycosylation of a major stress glycoprotein, GP62 (Mr of 62,000). We further purified GP62 by sequential preparative isoelectric focusing and two-dimensional isoelectric focusing/SDS-polyacrylamide gel electrophoresis. The purified protein was digested and partially characterized by microsequencing of two peptide fragments, comprising of 14-15 amino acids each. These fragments had a 100% sequence homology with HSP70 and a 71-100% sequence homology with HSC70 from various species. Western blotting using both HSP70 and HSC70 antibodies showed positive reactivity of GP62 with HSP70. Affinity characterizations showed strong binding of GP62 to wheat germ agglutinin and concanavalin A, consistent with the presence of both alpha-D-mannosyl/glucosyl and N-acetyl-beta-D-glucosylaminyl/glucosamine oligomer residues in GP62. These data confirm the glycosylated status of GP62 and indicate that GP62 is a heat stress-induced glycoprotein with partial homology to HSP70.


Impact of Artificial Sputum Medium Formulation on Pseudomonas aeruginosa Secondary Metabolite Production.
In vitro culture media are being developed to understand how host site-specific nutrient profiles influence microbial pathogenicity and ecology. To mimic the cystic fibrosis (CF) lung environment, a variety of artificial sputum media (ASM) have been created. However, the composition of these ASM vary in the concentration of key nutrients, including amino acids, lipids, DNA, and mucin. In this work, we used feature-based molecular networking (FBMN) to perform comparative metabolomics of Pseudomonas aeruginosa, the predominant opportunistic pathogen infecting the lungs of people with CF, cultured in nine different ASM. We found that the concentration of aromatic amino acids and iron from mucin added to the media contributes to differences in the production of P. aeruginosa virulence-associated secondary metabolites. IMPORTANCE Different media formulations aiming to replicate in vivo infection environments contain different nutrients, which affects interpretation of experimental results. Inclusion of undefined components, such as commercial porcine gastric mucin (PGM), in an otherwise chemically defined medium can alter the nutrient content of the medium in unexpected ways and influence experimental outcomes.


Fabrication of Hybrid Capsules via CaCO3 Crystallization on Degradable Coacervate Droplets.
Organic-inorganic CaCO3 capsules were prepared by crystallization of CaCO3 on Pickering emulsion prepared using coacervate droplets made from thermoresponsive and degradable poly(2-methylene-1,3-dioxepane- co-2-hydroxyethyl acrylate) (poly(MDO- co-HEA)) in sole aqueous medium. The diameters of CaCO3-based Pickering emulsion could be controlled by varying several parameters: diameter of CaCO3 powders, initial polymer concentration, and copolymer composition. The CaCO3 Pickering emulsion was able to load low-molecular-weight hydrophobic substances at temperatures above the lower critical solution temperature (LCST) due to formation of polymer-concentrated phases, i.e., coacervate droplets. The diameter of CaCO3 capsules prepared by crystallization also depended on the diameter of the CaCO3 Pickering emulsion. The CaCO3 shell was composed of calcite-type crystals, the most stable polymorph among known CaCO3 crystals. The facially prepared CaCO3 capsules are valuable for use in functional biomaterials, such as drug delivery carriers and cell culture scaffolds for noninvasive bone-regenerative medicine.


Efficacy of fluconazole (UK-49,858) against experimental aspergillosis and cryptococcosis in mice.
The efficacy of fluconazole, a new bis-triazole antifungal agent, was compared with that of orally administered ketoconazole and parenterally administered amphotericin B against aspergillus and cryptococcus infections in mice. Fluconazole was 5-20-fold more active than ketoconazole against systemic aspergillosis and against systemic, intracranial and pulmonary cryptococcosis but was less active than amphotericin B.


Effect of pork quality and salt replacer KCl on technological and sensorial characteristics of restructured cooked hams.
The aim of this study was to evaluate the effects of replacing sodium chloride (NaCl) by 40% of potassium chloride (KCl), combined to the use of different proportions (0, 50, and 100%) of pale, soft, and exudative meat, on the technological and sensorial characteristics of restructured cooked hams. NaCl replacement and pale, soft, and exudative proportion did not change (P > 0.05) the products' chemical composition, water losses, pH, and color. The ham texture profile was not affected by pale, soft, and exudative meat, but the chewiness reduced (P < 0.05) with NaCl replacement. Pale, soft, and exudative meat reduced (P < 0.05) the ham sliceability from 94 to 88%, regardless of the proportion used. NaCl replacement did not affect the perceived saltiness and the products' acceptability, but pale, soft, and exudative products were more accepted, and consumers noticed a higher salty taste. It was concluded that reducing the sodium content by partially replacing NaCl with KCl is feasible even in restructured cooked hams made with high proportions of pale, soft, and exudative meat.


Absence of association between TNF-α polymorphism and cerebral large-vessel abnormalities in adults with sickle cell anemia.
Stroke is a serious complication of sickle cell anemia (SCA) affecting children and adults. Recent reports suggested that tumor necrosis factor-α (TNF-α) (-308) polymorphism is an important risk factor for stroke in children with SCA. The role of TNF-α polymorphism in the frequency of brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) abnormalities in adults with SCA is still uncertain. Our objective was to evaluate the frequency of TNF-α polymorphism in adults with SCA and to correlate it to brain MRI and MRA findings. TNF-α (-308) polymorphism was determined in 49 adults with SCA. All subjects were evaluated with brain MRI/MRA to establish the presence of intracranial abnormalities. Thirty-three (67.3%) had abnormal brain MRA scans, 8 (16.3%) had intracranial stenosis and 29 (59.2%) showed arterial tortuosity. Forty-one (83.7%) had the GG genotype and 8 had the GA genotype. There was no correlation between homozygosity for G allele and MRA or MRI abnormalities. Although TNF-α (-308) polymorphism is a potential predictor of the genetic risk for stroke in children, we found no association between the polymorphism and large vessel abnormalities in adults with SCA.


Computational Modeling of the Chlamydial Developmental Cycle Reveals a Potential Role for Asymmetric Division.
Chlamydia trachomatis is an obligate intracellular bacterium that progresses through an essential multicell form developmental cycle. Infection of the host is initiated by the elementary body (EB). Once in the host, the EB cell differentiates into the noninfectious, but replication-competent, reticulate body, or RB. After multiple rounds of replication, RBs undergo secondary differentiation, eventually producing newly infectious EBs. Here, we generated paired cell-type promoter reporter constructs and determined the kinetics of the activities of the euo, hctA, and hctB promoters. The paired constructs revealed that the developmental cycle produces at least three phenotypically distinct cell types, the RB (euoprom+), intermediate body (IB; hctAprom+), and EB (hctBprom+). The kinetic data from the three dual-promoter constructs were used to generate two computational agent-based models to reproduce the chlamydial developmental cycle. Both models simulated EB germination, RB amplification, IB formation, and EB production but differed in the mechanism that generated the IB. The direct conversion and the asymmetric production models predicted different behaviors for the RB population, which were experimentally testable. In agreement with the asymmetric production model, RBs acted as stem cells after the initial amplification stage, producing one IB and self-renewing after every division. We also demonstrated that IBs are a transient cell population, maturing directly into EBs after formation without the need for cell division. The culmination of these results suggests that the developmental cycle can be described by a four-stage model, EB germination, RB amplification/maturation, IB production, and EB formation. IMPORTANCE Chlamydia trachomatis is an obligate intracellular bacterial pathogen responsible for both ocular and sexually transmitted infections. All Chlamydiae are reliant on a complex developmental cycle, consisting of both infectious and noninfectious cell forms. The EB cell form initiates infection, whereas the RB cell replicates. The infectious cycle requires both cell types, as RB replication increases the cell population while EB formation disseminates the infection to new hosts. The mechanisms of RB-to-EB development are largely unknown. Here, we developed unique dual promoter reporters and used live-cell imaging and confocal microscopy to visualize the cycle at the single-cell and kinetic levels. These data were used to develop and test two agent-based models, simulating either direct conversion of RBs to EBs or production of EBs via asymmetric RB division. Our results suggest that RBs mature into a stem cell-like population producing intermediate cell forms through asymmetric division, followed by maturation of the intermediate cell type into the infectious EB. Ultimately, a more complete mechanistic understanding of the developmental cycle will lead to novel therapeutics targeting cell type development to eliminate chlamydial dissemination.


The fox operon from Rhodobacter strain SW2 promotes phototrophic Fe(II) oxidation in Rhodobacter capsulatus SB1003.
Anoxygenic photosynthesis based on Fe(II) is thought to be one of the most ancient forms of metabolism and is hypothesized to represent a transition step in the evolution of oxygenic photosynthesis. However, little is known about the molecular basis of this process because, until recently (Y. Jiao and D. K. Newman, J. Bacteriol. 189:1765-1773, 2007), most phototrophic Fe(II)-oxidizing bacteria have been genetically intractable. In this study, we circumvented this problem by taking a heterologous-complementation approach to identify a three-gene operon (the foxEYZ operon) from Rhodobacter sp. strain SW2 that confers enhanced light-dependent Fe(II) oxidation activity when expressed in its genetically tractable relative Rhodobacter capsulatus SB1003. The first gene in this operon, foxE, encodes a c-type cytochrome with no significant similarity to other known proteins. Expression of foxE alone confers significant light-dependent Fe(II) oxidation activity on SB1003, but maximal activity is achieved when foxE is expressed with the two downstream genes foxY and foxZ. In SW2, the foxE and foxY genes are cotranscribed in the presence of Fe(II) and/or hydrogen, with foxZ being transcribed only in the presence of Fe(II). Sequence analysis predicts that foxY encodes a protein containing the redox cofactor pyrroloquinoline quinone and that foxZ encodes a protein with a transport function. Future biochemical studies will permit the localization and function of the Fox proteins in SW2 to be determined.


Influence of Offset on Hemodynamics of Intra-atrial Conduit Fontan's Procedure and Its Clinical Implications.
The desirable distance, defined as offset, between the central line of the superior vena cava (SVC) and the intra-atrial conduit after an intra-atrial conduit (IAC) Fontan's procedure remained unclear. We compared the hemodynamic features using virtual surgery with different offset designs in our study. Three-dimensional models of IAC Fontan's procedure were reconstructed according to the magnetic resonance imagings (MRIs) of three patients, then four models for each patient with different offsets equaling 100, 67, 33, and 0% of the diameter of the IVC were reconstructed. Computational fluid dynamics (CFD) were performed in each model to predict the best hemodynamic features, including streamlines of blood flow, wall shear stress (WSS), energy loss (EL), and the hepatic flow distribution (HFD) ratio. Comprehensive evaluation of WSS, EL, and HFD revealed than an offset of 33% presents the best hemodynamic performance among the three patients modeled. In patient A, an offset of 33% resulted in the best HFD (left pulmonary artery/right pulmonary artery [LPA/RPA] = 35/65%). In patient B, the best trade-off between HFD (35/65%), and WSS was achieved with an offset of 33%. In patient C, EL peaked at an offset of 0% and significantly dropped at an offset of 33% with a desirable HFD (60/40%). We verified that the offset distance influences hemodynamic performance in IAC Fontan's procedure. Considering several hemodynamic parameters, the best trade-offs between hemorheology, pulmonary perfusion, and energy efficiency were achieved at an offset of 33%. This distance should be taken into consideration and optimized during the surgical planning for the IAC Fontan's procedure.


Controllable Mn-doped ZnO nanorods for direct assembly of a photoelectrochemical aptasensor.
A label-free photoelectrochemical (PEC) aptasensor for K+ was first constructed by direct self-assembly of the K+ aptamer onto the electrodeposited Mn-doped ZnO nanorods. In the presence of K+, the conformation of G-quadruplex changes to a K+-stabilized conformation, which can efficiently prevent the quercetin electron donor from reaching the functionalized photoanode, thus proportionately affecting the quercetin-enhanced photocurrent response. Under the optimal experimental conditions, the fabricated biosensor exhibited a linear response in the K+ concentration range of 0.012 to 12.32 nmol L-1, with a detection limit of 4.0 pmol L-1, which was 3-5 orders of magnitude lower than that of most of the recently reported methods. The presence of other ions did not interfere with the detection of K+, and the results in serum samples agreed well with those obtained by ICP-MS. Using K+ as the detection model, this novel PEC aptasensor exhibited a good performance in terms of ultrasensitivity, selectivity and simplicity, and it was economical. As regards the electrode modification, this work provided a convenient direct self-assembly strategy that did not require the use of ionic polymers such as PDDA as a binder. Thus, this study paves the way for the immobilization of molecular probes for label-free PEC aptasensing.


Herbaceous Angiosperms Are Not More Vulnerable to Drought-Induced Embolism Than Angiosperm Trees.
The water transport pipeline in herbs is assumed to be more vulnerable to drought than in trees due to the formation of frequent embolisms (gas bubbles), which could be removed by the occurrence of root pressure, especially in grasses. Here, we studied hydraulic failure in herbaceous angiosperms by measuring the pressure inducing 50% loss of hydraulic conductance (P50) in stems of 26 species, mainly European grasses (Poaceae). Our measurements show a large range in P50 from -0.5 to -7.5 MPa, which overlaps with 94% of the woody angiosperm species in a worldwide, published data set and which strongly correlates with an aridity index. Moreover, the P50 values obtained were substantially more negative than the midday water potentials for five grass species monitored throughout the entire growing season, suggesting that embolism formation and repair are not routine and mainly occur under water deficits. These results show that both herbs and trees share the ability to withstand very negative water potentials without considerable embolism formation in their xylem conduits during drought stress. In addition, structure-function trade-offs in grass stems reveal that more resistant species are more lignified, which was confirmed for herbaceous and closely related woody species of the daisy group (Asteraceae). Our findings could imply that herbs with more lignified stems will become more abundant in future grasslands under more frequent and severe droughts, potentially resulting in lower forage digestibility.


Remote, Disconnected, or Detached? Examining the Effects of Psychological Disconnectedness and Cynicism on Employee Performance, Wellbeing, and Work-Family Interface.
Owing to the COVID-19 pandemic, organizations worldwide have implemented remote working arrangements that have blurred the work-family boundaries and brought to the forefront employees' sense of disconnectedness from their workplace (i.e., organizational disconnectedness) as a concern for multiple organizational outcomes. Cynicism, a job burnout subdimension, refers to a negative and excessively detached response to relational overload at work. While both workplace disconnectedness and cynicism involve a toxic sense of detachment, they refer to different psychological mechanisms. The present study aims to examine how employee workplace disconnectedness differs from their cynicism, and how both constructs differentially exert their detrimental effects on employee performance, work-family interface, and wellbeing. Using anonymous survey data collected online in 2021 and 2022 from a sample of in-person and flexible workers nested within organizations, conceptual distinctiveness between workplace disconnectedness and cynicism was supported. Measurement invariance across the two groups was supported, and subsequent structural invariance analyses suggested a similar pattern of results for flexible and in-person workers. Specifically, compared to disconnectedness, cynicism exerted higher negative effects on mental health and higher positive effects on cognitive failures and family-to-work conflict. Conversely, compared to cynicism, disconnectedness exerted higher negative effects on performance and work-to-family conflict. That is, feeling indifferent toward others particularly affects mental health and errors, while feeling excluded especially hampers productivity and family life. Theoretical and practical (e.g., inclusive leadership, support groups) implications of these results are discussed in light of the globally rising rates of hybrid work arrangements and related costs for employee wellbeing and productivity.


Resolving an anomaly between measured spectral linewidths of n=3 transitions in N II and O III spectra.
A reported anomaly in the experimental scaling of the widths of Stark broadened n=3, Delta n=0 spectral lines along the carbon isoelectronic sequence is not observed in the present experiments. The ratio omega(N)/omega(O) of widths for N II lines compared to those for the narrower O III lines for the same transitions is now measured as lying between two theoretical predictions, both of which show a value omega(z-1)/omega(z) greater than unity continuing throughout the sequence. In the earlier measurements, the widths (in frequency units) were actually measured as being smaller for N II than for O III, i.e., a ratio omega(z-1)/omega(z) less than unity.


Evaluation of diagnostic tests for influenza in a pediatric practice.
Recent advances in the diagnosis and treatment of influenza virus infections include: (1) rapid bedside diagnosis methods with simple commercially available tests; and (2) Food and Drug Administration approval of treatment for children 1 year of age and older with neuraminidase inhibitor drugs. For proven benefit antivirals should be used within 2 days of onset of symptoms. We conducted a performance improvement exercise comparing the sensitivity and specificity of four rapid tests for influenza viruses: (1) Flu OIA (Biostar); (2) Quickvue Influenza Test (Quidel); (3) Z Stat Flu (ZymeTx); and (4) Directigen Flu A (Becton Dickinson). During the 1999 to 2000 epidemic, symptomatic patients seen at the private practice of one of the authors provided specimens collected and processed according to the manufacturer's directions. Throat swabs only were used to collect the specimens for the Z Stat Flu Kit. Directigen was performed immediately, and the others were run in parallel within 12 to 24 h. Specimens were frozen first at -20 degrees C for up to 3 days and shipped in transport medium to the Virology Research Laboratory of the Virginia State Health Department for culture where they were stored at -60 degrees C until cultured. Some of the samples were processed by a commercial laboratory. Specimens from 116 patients were available for influenza culture; for 88 of these culture was performed at the State Health Department Laboratory, and for 28 culture was performed at a local commercial medical laboratory. Influenza virus (A) was detected in 58 of 116 (50%) specimens, 10 (17%) of these only by direct fluorescent antigen samples. Viral culture-direct fluorescent antigen results were used as the standard. Of the 4 tests Biostar and Z Stat Flu required more technician time (by an average of 2-fold). The 4 tests had sensitivities ranging from 72 to 95%. Z Stat differed significantly in sensitivity from the other three (P = 0.001). The specificities of Directigen, Quickvue, Flu OIA and Z Stat Flu were similar (76 to 86%). The positive predictive value of Directigen, Quickvue and FluOIA and Z Stat ranged from 80 to 86%. The negative predictive value of all 4 tests ranged from 75 to 94%. Z Stat Flu had a lower negative predictive value than the other 3 tests (75%; P = 0.001. In this first head-to-head comparison of four rapid diagnostic tests for influenza, Directigen Flu A, Quickvue and Flu OIA appear equivalent in sensitivity, specificity, positive predictive value and negative predictive value. Z Stat Flu was not as sensitive or as efficient as the other three tests.


Supramalleolar Osteotomy With Distraction Arthroplasty in Treatment of Varus Ankle Osteoarthritis With Large Talar Tilt Angle: A Case Report and Literature Review.
We treated a 57-year-old female with modified Takakura stage 3B varus ankle osteoarthritis. Her preoperative talar tilt angle was 21.3°. The patient wished to avoid ankle joint arthrodesis or replacement. Therefore, medial opening wedge supramalleolar osteotomy with fibular osteotomy was used for her varus ankle osteoarthritis. Also, fixed medial distraction arthroplasty was performed to improve her talar tilt. After 3 months, the external device was removed, and the patient was allowed partial weightbearing and began full weightbearing 4 months postoperatively after the osteotomy site had reached bony union radiographically. At the 3-year follow-up visit, a radiograph showed the medial ankle joint space enlargement had been maintained. The talar tilt angle had decreased to 3.3°, and the modified Takakura stage had improved to stage 1. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scale score had improved from 26 points preoperatively to 85 points at 3 years postoperatively. Our findings suggested that good clinical and radiologic results can be achieved with supramalleolar osteotomy combined with distraction arthroplasty in the treatment of varus ankle osteoarthritis with a large talar tilt angle.


[Minimally invasive surgery for cancer arising in a reconstructed gastric tube after esophagectomy based on evaluation of blood and lymphatic flow by indocyanine green fluorescence imaging].
A 69-year-old man was admitted to our hospital for treatment of gastric tube cancer detected by screening upper gastrointestinal endoscopy. Seven years previously, he had undergone subtotal esophagectomy for esophageal cancer with gastric pull-up via the retrosternal route. Contrast study revealed a filling defect in the distal part of the reconstructed gastric tube. Nasopharyngeal cancer was detected at the same time. After chemoradiotherapy for nasopharyngeal cancer, surgery was performed for gastric tube cancer. Because the radiation field included the anastomotic site of the pervious surgery, resection of the distal part of the gastric tube was considered. For this purpose, we intraoperatively evaluated blood and lymphatic flow along the gastric tube by using indocyanine green (ICG) fluorescence imaging. Submucosal ICG injection around the tumor revealed lymphatic flow localized around the right gastroepiploic artery. In addition, intravenous ICG injection revealed blood flow from the oral side of the gastric tube into the distal part. Based on this finding, we performed distal gastrectomy (resection of the distal part of the gastric tube) with Roux-en-Y reconstruction (gastro-jejunal anastomosis). The postoperative course was uneventful. On histological examination, the tumor was diagnosed as pT1b (SM) N0M0, pStage IA. Intraoperative evaluation of blood and lymphatic flow using ICG fluorescence imaging is useful during minimally invasive surgery for cancer in a reconstructed gastric tube.


Genetic Polymorphisms in CD35 Gene Contribute to the Susceptibility and Prognosis of Hepatocellular Carcinoma.
CD35, an important molecule implicated in inflammation and immunity, is reportedly associated with several cancers. However, very few studies have investigated the relationship between CD35 polymorphisms and hepatocellular carcinoma (HCC). The current study was conducted to investigate the association between tag SNPs in CD35 and HCC susceptibility and postoperative recurrence, in an attempt to elucidate the gene-environment interactions in HCC. A total of 1233 Chinese Han people, including 647 healthy controls and 586 HCC cases, were sampled in this study. Six Tag SNPs (rs10494885, rs2296160, rs3737002, rs3849266, rs669117, and rs7525160) of CD35 were selected using the HaploView 4.2 program and genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Overall, the mutation genotypes CC/CG of CD35 rs7525160 significantly increased the risk of HCC. Stratification analysis indicated that CD35 rs7525160 CC/CG genotypes increased HCC risk in patients younger than 65 years and were closely related to the pathological type of poor prognosis of HCC. Cox proportional hazard ratio model analysis revealed that the rs7525160 CC/CG genotype remains a significant independent risk factor for postoperative recurrence of HCC. In conclusion, CD35 rs7525160 polymorphism may contribute to the susceptibility and prognosis of HCC in the Chinese Han population.


Rheological properties of a two phase lipid monolayer at the air/water interface: effect of the composition of the mixture.
Many biologically relevant monolayers show coexistence of discrete domains of a long-range ordered condensed phase dispersed in a continuous, disordered, liquid-expanded phase. In this work, we determined the viscous and elastic components of the compressibility modulus and the shear viscosity of monolayers exhibiting phase coexistence with the aim at elucidating the contribution of each phase to the observed monolayer mechanical properties. To this purpose, mixed monolayers with different proportions of distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC) were prepared and their rheological properties were analyzed. The relationship between the phase diagram of the mixture at 10 mN m(-1) and the rheological properties was studied. We found that the monolayer shear viscosity is highly dependent on the presence of domains and on the domain density. In turn, the monolayer compressibility is only influenced by the presence of domains for high domain densities. For monolayers that look homogeneous on the micrometer scale (DSPC amount lower that 23 mol %), all the analyzed rheological properties remain similar to those observed for pure DMPC monolayers, indicating that in this proportion range the DSPC molecules contribute as DMPC to the surface rheology in spite of having hydrocarbon chains four carbons longer.


13q deletion in chronic lymphocytic leukemia: characterization of E4.5, a novel chromosome condensation regulator-like guanine nucleotide exchange factor.
We report the characterization of a new gene (E4.5) that maps at chromosome band 13q14.3, a chromosomal area frequently deleted in chronic lymphocytic leukemia (CLL) and in other lymphoid malignancies. E4.5 gene encodes for a 4 kb mRNA expressed in various tissues and has an open reading frame of 531 amino acids. The predicted E4.5 protein shows strong homology with the human regulator of chromosome condensation (RCC1) protein, the principal GTP exchange factor for Ran protein. The E4.5 protein contains a BTB domain in its N-terminus, a protein-protein interaction motif. Therefore, we propose that E4.5 is a new member of the RCC1-related guanine nucleotide exchange factor (GEF) family with potent interaction with other proteins and unknown function. Until now, no tumor suppressor genes have been mapped in the 13q14.3 minimal deleted region (MDR) in patients with CLL. It has been proposed that loss of the 13q14.3 MDR may contribute to lymphoid neoplasia by altering the expression/function of genes located on 13q14.3 outside the MDR. The E4.5 is one of these genes with a potential role in the pathogenesis of CLL.


Tropane alkaloid production in Datura stramonium suspension cultures: elicitor and precursor effects.
The effects of elicitation, carbon, and nitrogen sources, and precursors on cell growth and tropane alkaloid production in Datura stramonium cell cultures were studied. D. Stramonium cell cultures responded very well to elicitors in the late exponential phase. Addition of cell wall fragments of Phytophotora megasperma (Pmg) enhanced the final tropane alkaloid yield by fivefold compared with control culture. Supply of carbon culture. Supply of carbon and nitrogen sources, at a ratio (C/N) of up to 70, to cell cultures in the early stationary phase, suppressed tropane alkaloid production; whereas C/N rations beyond about 100 increased the final product yield by more than 100% compared to that of the control experiment. Total alkaloid production in the cell culture supplemented with phenylalanine and ornithine was five times higher that that in the control culture. Higher rations of tropine to tropic acid also stimulated alkaloid production. At a ratio of 20, the productivity was seven times higher that that in the control culture. Adding precursors at high concentrations (e.g., 3 to 10 mM) to the cell culture reduced the final cell yield by less than 40%, while elicitation did not affect the cell yield. On the other hand, cell yield in the cultures supplemented with carbon and nitrogen sources was influenced by the C/N ratio. The highest cell yield was obtained at C/N = 70.


The role of footwear in minimizing lower limb injury.
The shoe can be thought of as a powerful tool for controlling human movement. A well-designed shoe can assist in reducing the number of lower limb injuries arising from sport and training activities. The purpose of this paper is to present a summary of the main thrusts of research in this field by means of a digest of current thinking and practice. The paper initially presents a survey of work in the biomechanical field with particular reference to the design of footwear. A review of the types of injury acquired by sportsmen in both training and playing is then followed by a discussion of aspects of footwear design and their role in both contributing to and preventing lower limb injury. Finally, the paper considers support and shock absorption techniques in the context of footwear design. It is concluded that research has been wide-ranging and thorough. However, the complexity of the biomechanical system being studied has prevented definitive recommendations for the prevention of injury being made in every case. Nonetheless, it is clear that a number of guiding principles have been established which should be the basis for future developments in footwear design to minimize the chance of lower limb injury.


Genomic profiling of human penile carcinoma predicts worse prognosis and survival.
The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copy-number alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT-qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1-p14.3 and gains of 3q25.31-q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status.


Formation and metabolism of leukotriene C4 in macrophages exposed to bacterial lipopolysaccharide.
Lipopolysaccharide (10 micrograms/ml) was found to stimulate resident mouse peritoneal macrophages to produce leukotriene C4 (36 +/- 1.3 ng/10(6) cells, SEM, n = 20) within 16 h. Spontaneous synthesis in control cultures without lipopolysaccharide was less than 1.6 ng/10(6) cells. Leukotriene C4 was characterized by reversed-phase high-performance liquid chromatography, ultraviolet spectrometry and radioimmunoassay. When the macrophages, prelabeled with [3H]arachidonic acid, were treated with lipopolysaccharide radioactivity was incorporated into leukotriene C4. The amount produced varied with the method of macrophage preparation and incubation conditions and was dependent on the amount of lipopolysaccharide added (0.5-60 micrograms/ml), on cell counts and on the incubation time (4-16 h). The released leukotriene C4 was converted to a compound identified as a C6-cysteinylleukotriene, indicating metabolism of the leukotriene by the macrophages. Parallel determinations of prostaglandins E2 and F2 alpha by radioimmunoassay demonstrated that leukotriene C4 and prostaglandin E2 are formed by mouse peritoneal macrophages to a similar degree.


The modulatory effect of anti-idiotypic antibody on hybridoma cells secreting antibody to human myelin basic protein peptide 80-89.
The idiotype (ID) of an antibody is postulated to be involved in immunoregulation by means of the immune network. This hypothesis was examined by studying the effect of a monoclonal antibody (MAb) anti-ID on hybridoma cells secreting an ID-bearing MAb, 845D3, to human myelin basic protein (MBP) peptide 80-89. The monoclonal anti-ID (IgM/kappa), reacted with heavy and light chains of 845D3, an IgG1/kappa MAb, but not with a control MAb of the same isotype specific for an MBP peptide differing by one amino acid residue. Fluorescence-activated cell sorting revealed IgG heavy and kappa light chains on the surface and in the cytoplasm of 90% or more of the 845D3 cells. The anti-ID did not react with the surface of the 845D3-secreting cells, and reacted with the cytoplasm of 14-18% of these cells. In spite of the absence of cell surface ID, the anti-ID significantly decreased antibody production by the ID-secreting cells. There was no effect of the anti-ID on control hybridoma cells secreting MAb to another MBP cells. There was no effect of the anti-ID on control hybridoma cells secreting MAb to another MBP peptide. Anti-ID exerted no cytotoxic effect on ID-bearing hybridoma cells and in fact caused a marginal increase in their proliferation compared to control MAb. These results indicate that an anti-ID may alter the antibody production of ID-secreting cells in a specific manner and without cytotoxicity. This may be one of the means for controlling an immune response against MBP generated by the cells of the immune system or in situ within the nervous system. The cellular mechanism(s) for this effect remains to be defined.


Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344.
This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.


Visible-Light Photoreduction of CO2 in a Metal-Organic Framework: Boosting Electron-Hole Separation via Electron Trap States.
It is highly desirable to convert CO2 to valuable fuels or chemicals by means of solar energy, which requires CO2 enrichment around photocatalysts from the atmosphere. Here we demonstrate that a porphyrin-involved metal-organic framework (MOF), PCN-222, can selectively capture and further photoreduce CO2 with high efficiency under visible-light irradiation. Mechanistic information gleaned from ultrafast transient absorption spectroscopy (combined with time-resolved photoluminescence spectroscopy) has elucidated the relationship between the photocatalytic activity and the electron-hole separation efficiency. The presence of a deep electron trap state in PCN-222 effectively inhibits the detrimental, radiative electron-hole recombination. As a direct result, PCN-222 significantly enhances photocatalytic conversion of CO2 into formate anion compared to the corresponding porphyrin ligand itself. This work provides important insights into the design of MOF-based materials for CO2 capture and photoreduction.


Mapping of Podoconiosis Cases and Risk Factors in Kenya: A Nationwide Cross-sectional Study.
Podoconiosis is a type of tropical lymphedema that is clinically distinguished from lymphatic filariasis (LF) because it is ascending and commonly bilateral but asymmetric. The disease is a result of a genetically determined inflammatory reaction to long-term exposure to mineral particles in irritant red clay soils derived mainly from volcanic soils. We conducted the first nationwide mapping of the prevalence and risk factors of podoconiosis in Kenya. We performed a population-based cross-sectional survey to determine the national prevalence of podoconiosis and included 6,228 individuals from 48 villages in 24 sub-counties across 15 counties. Participants answered a questionnaire about the history of symptoms compatible with podoconiosis, received a point-of-care antigen test, and underwent a physical examination if they had lymphedema. A confirmed case of podoconiosis was defined as a case in a resident of the study village who had lower limb bilateral and asymmetric lymphedema lasting more than 1 year, negative test results for Wuchereria bancrofti antigen, and other causes of lymphedema ruled out. Of all the individuals surveyed, 89 had lymphedema; of those, 16 of 6228 (0.3%; 95% confidence interval [CI], 0.1-0.5) were confirmed to have podoconiosis. A high prevalence of podoconiosis was found in western (Siaya, 3.1%; Busia, 0.9%) and central (Meru, 1.1%) regions, and a low prevalence was observed in northern (Marsabit, 0.2%), eastern (Makueni, 0.2%), and coastal (Tana River, 0.1%) regions. The identified risk factors were age 56 years or older (adjusted odds ratio [aOR], 5.66; 95% CI, 2.32-13.83; P < 0.001) and rarely wearing shoes (aOR, 18.92; 95% CI, 4.55-78.71; P < 0.001). These results indicated that the podoconiosis prevalence is low and localized in Kenya; therefore, elimination is achievable if appropriate disease prevention, management, and behavioral strategies are promoted.


Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders.
Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp ) and genetic associations (rg ), as well as the contribution of genetic influences to rp . The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg = 0.73; 95% CI = 0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (rg = 0.47; 95% CI = 0.33-0.61), depression (rg = 0.52; 95% CI = 0.37-0.66), and intentional self-harm (rg = 0.54; 95% CI = 0.36-0.71). ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.


Timed release analgesics: Part 1. Narcotics.
The problem of relieving patients' pain is a major challenge for health care professionals. New formulations of time-released pain medications offer exciting possibilities. However, there are cautions and patient education factors that are important when considering any timed-release product. This article looks at selected timed-release forms of narcotics used for pain relief. Knowledge of the differences and similarities, benefits and cautions, and patient education factors will help the reader make safer and more informed decisions about prescribing and administering timed-release narcotics.


Obstructed labour in resource-poor settings: the need for revival of symphysiotomy in Nigeria.
Symphysiotomy is an operation in which the fibres of the pubic symphysis are partially divided to allow separation of the joint and thus enlargement of the pelvic dimensions thereby facilitating vaginal delivery of the foetus in the presence of mild to moderate cephalopelvic disproportion. It is performed with local anaesthesia, does not require an operating theatre or advanced surgical skills. It can be a lifesaving procedure for both mother and baby in obstructed labour, especially in rural areas and resource-poor settings of developing countries, where a 24 hours availability of a caesarean section cannot be guaranteed. It is a simple underused technology that can be performed by a graduate doctor or midwife in rural health facilities and hospitals where most of the times, in Nigeria, there are no practicing specialist obstetricians. In rural hospital and in communities where sympysiotomy is still being performed, it is evident that it is preferred to caesarean section because of the socio-cultural desire to achieve a vaginal delivery. This paper highlights our experiences with symphysiotomy in a rural Roman Catholic hospital providing evidence on the safety of symphysiotomy and the need for its revival and reinstatement in the obstetric arsenal in Nigeria and similar countries in sub-Saharan Africa where maternal mortality as a result of prolonged and neglected obstructed labour still occur.


Intramyocardial Injection of Recombinant Adeno-Associated Viral Vector Coexpressing PR39/Adrenomedullin Enhances Angiogenesis and Reduces Apoptosis in a Rat Myocardial Infarction Model.
Cotransfer of angiogenic and antiapoptotic genes could be the basis of new gene therapy strategies for myocardial infarction. In this study, rAAV-PR39-ADM, coexpressing antimicrobial peptide (PR39) and adrenomedullin (ADM), was designed with the mediation of recombinant adeno-associated virus. In vitro, CRL-1730 cells were divided into four groups, namely, the sham group, the AAV-null group, the NS (normal saline) group, and the PR39-ADM group. Immunocytochemistry analysis, CCK-8 assays, Matrigel assays, and apoptotic analysis were performed; in vivo, myocardial infarction model was established through ligation of the left coronary artery on rats, and treatment groups corresponded to those used in vitro. Myocardial injury, cardiac performance, and the extent of myocardial apoptosis were assessed. Results suggested that rAAV-PR39-ADM administration after myocardial infarction improved cell viability and cardiac function, attenuated apoptosis and myocardial injury, and promoted angiogenesis. Subsequently, levels of 6×His, HIF-1α, VEGF, p-Akt, Akt, ADM, Bcl-2, and Bax were measured by western blot. rAAV-PR39-ADM increased p-Akt, HIF-1α, and VEGF levels and induced higher Bcl-2 expression and lower Bax expression. In conclusion, our results demonstrate that rAAV-PR39-ADM mitigates myocardial injury by promoting angiogenesis and reducing apoptosis. This study suggests a potential novel gene therapy-based method that could be used clinically for myocardial infarction.


Medical Redeployment in Soldiers With and Without Medical Deployment Waivers.
Historically, disease and nonbattle injuries (DNBI) have caused more casualties during military operations than enemy combatants. Recent deployments to U.S. Central Commands (USCENTCOM) area of operation (AOR) have demonstrated similar outcomes. Intuitively, appropriate medical standards for our deploying Soldiers should result in no greater redeployments rates for those Soldiers who are waived for various medical conditions. However, no formal study has been published on redeployment rates of Soldiers with medical deployment waivers. The objective of this report was to evaluate the redeployment rates of Soldiers with and without medical waivers. A matched retrospective cohort study design was used in this study. Data were obtained from USCENTCOM, Army Central Command, Transportation Command, and the Armed Forces Health Surveillance Center. All U.S. Soldiers deploying to USCENTCOM's AOR with a medical deployment waiver during the calendar years of 2008-2013 were eligible for inclusion into the exposure group of this study. Soldiers with a medical deployment waiver were matched 1:5 to Soldiers without a medical deployment waiver. The Soldiers with a medical deployment waiver and their matched counterparts were then subdivided into 5 strata on the basis of their diagnosis. A McNemar's χ2 test was performed to calculate risk ratios (RRs) per strata and for the group as a whole. The overall risk of being medically evacuated because of DNBI for all medical deployment waivers was an RR of 2.03 (CI: 1.74, 2.36). The greatest risk of being medically evacuated because of DNBI was from the group of Soldiers on a waiver for neurological conditions with an RR of 3.81 (CI: 1.99, 7.30). The RR of medical evacuation because of DNBI was increased and statistically significant for all strata (p < 0.05). There is a statistically significant increased RR of Soldiers with a Modification of the Operational Order waiver being medically redeployed for a DNBI reason from USCENTCOM's AOR from 2008 to 2013 compared with their matched peers without a waiver. The results of this study provide Commanders with additional information when making decisions regarding Soldier deployment.


PEGylated Perylenemonoimide-Dithienylethene for Super-Resolution Imaging of Liposomes.
We have designed and synthesized an amphiphilic photoswitchable fluorophore, PEGylated perylenemonoimide-dithienylethene (PEG-PMI-DTE), which exhibits evident bistable photochromism, fluorescence switching, and fatigue resistance. The fine nanostructures of liposomes can be observed directly under super-resolution fluorescent microscopy by aid of the amphiphilic photoswitchable fluorophore as a staining agent, with an optical resolution of 30 nm.


Interactions of antiretroviral drugs with anti-infectives and other antiretrovirals.
Combination antiretroviral (ARV) treatment is a potent and effective therapy for human immunodeficiency virus infection. Unfortunately, ARV drugs frequently interact among themselves, as well as with other anti-infectives. These interactions determine positive or negative consequences resulting in recommendations to avoid some combinations or to adjust the dosage of coadministered drugs. The effective clinical use of ARVs requires deep knowledge of interaction mechanisms and the consequent recommendations when coadministering interacting ARVs with other anti-infectives. A brief review of the present knowledge on interactions of ARVs with anti-infective drugs is presented.


Comparison of glucose levels in capillary blood samples obtained from a variety of body sites.
The AtLast Blood Glucose System was developed to eliminate painful finger punctures by testing samples from less sensitive body sites. Studies were designed to evaluate subjects under various glycemic states and to compare glucose concentrations in samples obtained from the forearm and palm to those found in the finger. The palm is more similar to the finger in blood flow rates, while the forearm is less perfused. AtLast measurements of forearm samples from subjects at a minimum of 2 h postprandial produced good regression statistics when compared to reference finger results with a correlation coefficient of 0.978. Agreement was quite weakened in subjects undergoing extreme glucose loads, resulting in a slope of 0.85, an intercept of 30.82, and a correlation coefficient of 0.938. Time course data indicate that forearm glucose levels often appear lower than finger concentrations when glucose is rapidly rising and somewhat higher when glucose is quickly falling. On the other hand, glucose levels of palm samples produced a close correlation to finger concentrations under all glycemic states. In participants undergoing rapid glucose change, the linear correlation resulted in a slope of 1.01, an intercept of 2.46, and a high correlation coefficient of 0.983, with steady tracking of palm and finger concentrations throughout the study. The palm of the hand was also identified as a comfortable testing site that equals the forearm in affording painless testing. Glucose monitoring of blood samples from the forearm is suitable when expecting steady state glycemic conditions. At times of rapid glucose change, the palm of the hand offers a painless sampling site that compares well with the finger.


Comparing Antonovsky's sense of coherence scale across three UK post-industrial cities.
High levels of 'excess' mortality (ie, that seemingly not explained by deprivation) have been shown for Scotland compared to England and Wales and, especially, for its largest city, Glasgow, compared to the similarly deprived English cities of Liverpool and Manchester. It has been suggested that this excess may be related to differences in 'Sense of Coherence' (SoC) between the populations. The aim of this study was to ascertain whether levels of SoC differed between these cities and whether, therefore, this could be a plausible explanation for the 'excess'. Three post-industrial UK cities: Glasgow, Liverpool and Manchester. A representative sample of more than 3700 adults (over 1200 in each city). SoC was measured using Antonovsky's 13-item scale (SOC-13). Multivariate linear regression was used to compare SoC between the cities while controlling for characteristics (age, gender, SES etc) of the samples. Additional modelling explored whether differences in SoC moderated city differences in levels of self-assessed health (SAH). SoC was higher, not lower, among the Glasgow sample. Fully adjusted mean SoC scores for residents of Liverpool and Manchester were, respectively, 5.1 (-5.1 (95% CI -6.0 to -4.1)) and 8.1 (-8.1 (-9.1 to -7.2)) lower than those in Glasgow. The additional modelling confirmed the relationship between SoC and SAH: a 1 unit increase in SoC predicted approximately 3% lower likelihood of reporting bad/very bad health (OR=0.97 (95% CI 0.96 to 0.98)): given the slightly worse SAH in Glasgow, this resulted in slightly lower odds of reporting bad/very bad health for the Liverpool and Manchester samples compared to Glasgow. The reasons for the high levels of 'excess' mortality seen in Scotland and particularly Glasgow remain unclear. However, on the basis of these analyses, it appears unlikely that a low SoC provides any explanation.