Maternal and neonatal outcomes of successful Kielland's rotational forceps delivery.
To estimate the rates of early neonatal and maternal complications in a consecutive series of successful Kielland's rotational forceps deliveries. This was a retrospective cohort study of consecutive cases of successful rotational forceps deliveries performed in singleton pregnancies at 36 weeks of gestation or more in a tertiary referral center in Scotland, UK, from 2001 to 2008 (n=873). We also compared outcomes associated with successful rotational forceps deliveries in 2008 (n=150) with those of nonrotational forceps delivery (n=873), ventouse delivery (n=159), spontaneous vertex delivery (n=3,494), and emergency cesarean delivery (n=947). There was one stillbirth associated with a rotational forceps delivery. This was diagnosed before application of forceps. After rotational forceps deliveries, 58 of 872 (6.7%) of live-born neonates were admitted to the neonatal unit. Twenty-seven of 872 (3.1%) neonates had one or more complications that could be attributable to traumatic delivery and seven neonates (0.8%) had a diagnosis of neonatal encephalopathy. When compared with alternative methods of delivery over a single year, neonatal admission rates after delivery by rotational forceps deliveries (5 of 150 [3.3%]) were not significantly different from spontaneous vertex delivery (128 of 3,494 [3.7%; P=1.00]) or ventouse delivery (6 of 159 [3.8%; P=1.00]) and lower than emergency cesarean delivery (106 of 947 [11.2%; P=.002). Postpartum hemorrhage rates after rotational forceps deliveries (8 of 150 [5.3%; P=.008]) were lower than those associated with emergency cesarean delivery (142 of 947 [15.0%; P=.008]). Rates of short-term neonatal and maternal complications after successful rotational forceps deliveries are low. II.


What differentiates declarative and procedural memories: reply to Cohen, Poldrack, and Eichenbaum (1997)
CPE claim that procedural and declarative representations differ on two important dimensions: flexibility and compositionality. I have proposed that the apparent flexibility of a memory depends entirely on the transfer conditions. Any retest is, in some sense, a test of flexibility, because something has changed since the original encoding episodic. I have argued that if one changes something that does not provide support to memory performance, the memory will appear flexible, and resistant to changes in the environment. If one changes the very thing that the representation codes, the memory will appear inflexible and easily disrupted by changes in the environment. This principle is equally true for procedural and declarative memory. CPE contend that procedural representations lack compositionality. An ideal test of this claim would examine the representation of a task that is widely agreed to be procedural (e.g. that has been demonstrated to be learned normally by amnesic patients, and in the absence of awareness by neurologically intact subjects). Such experiments appear not to have been conducted, and the fact is that many tasks that are widely agreed to be procedural probably are not compositional. They appear to be, as CPE contend, biases in a processing system; it is hard to imagine how repetition priming could be compositional. Nevertheless, this is not true of all procedural memories. There is a good deal of evidence that motor behaviour is organised hierarchically and has compositionality. There is every reason to think that most if not all motor behaviour is procedural; motor behaviour might be driven by goals that are declarative, but the low-level operations that actually manipulate effectors are closed to consciousness, do not depend on the medial temporal lobe or diencephalon, and would therefore be classified as procedural. CPE framed their theory of differences between procedural and declarative memory systems as an account of the deficit in amnesic patients. They therefore predict that the learning of amnesic patients should not show flexibility or compositionality. There is already at least one study showing learning in amnesic patients that is as flexible as that of control participants (Knowlton & Squire, 1996). There are not, to my knowledge, data on whether the motor skill learning of amnesic patients shows compositionality, but one might expect that it would, given that it does in neurologically intact participants, and given that motor skill learning appears unimpaired in amnesic patients. Thus, the conception of declarative and procedural memory provided by CPE may not provide a complete account of amnesic performance. The anatomic distinction between procedural and declarative memory systems appears quite strong, and there is therefore reason to believe that there are accompanying computational differences. There does not, however, appear to be sufficient evidence to support those differences proposed by CPE.


[Neuropathic pain as the reason for visiting Neurology: an analysis of its frequency].
Neuropathic pain (NP) is defined as pain that begins with or is caused by a primary injury or by a dysfunction in the nervous system. Our aim was to evaluate how often patients visit Neurology as outpatients with NP as the main reason for referral. A descriptive, cross sectional study was carried out on the use of the health care services; patients attended for the first time in a Neurology Screening visit were included consecutively. The variables studied were the following: the number of first visits and the total number of patients attended per visiting session, rate of patients with NP per visiting day, the topography and probable causation of the NP, and the rate of patients referred to the monographic NP clinic; the different quantitative variables are expressed in terms of their mean and standard deviation (SD), whereas the qualitative variables are given as their absolute value and the percentage. A total of 1,972 patients were attended, of whom 1,422 (72.1%) were first visits, with an average of 17.5 (SD: 2.5) new patients per visiting session. In all 113 patients clinically diagnosed with NP were identified, which represents a rate of 7.95% of the first visits. NP may be among the most frequent causes of the demand for neurological ambulatory care. The most common causes of NP were found to be trigeminal neuralgia, post-herpes neuralgia and diabetic polyneuropathy.


The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly.
ASAP1 (ADP ribosylation factor [ARF]- GTPase-activating protein [GAP] containing SH3, ANK repeats, and PH domain) is a phospholipid-dependent ARF-GAP that binds to and is phosphorylated by pp60(Src). Using affinity chromatography and yeast two-hybrid interaction screens, we identified ASAP1 as a major binding partner of protein tyrosine kinase focal adhesion kinase (FAK). Glutathione S-transferase pull-down and coimmunoprecipitation assays showed the binding of ASAP1 to FAK is mediated by an interaction between the C-terminal SH3 domain of ASAP1 with the second proline-rich motif in the C-terminal region of FAK. Transient overexpression of wild-type ASAP1 significantly retarded the spreading of REF52 cells plated on fibronectin. In contrast, overexpression of a truncated variant of ASAP1 that failed to bind FAK or a catalytically inactive variant of ASAP1 lacking GAP activity resulted in a less pronounced inhibition of cell spreading. Transient overexpression of wild-type ASAP1 prevented the efficient organization of paxillin and FAK in focal adhesions during cell spreading, while failing to significantly alter vinculin localization and organization. We conclude from these studies that modulation of ARF activity by ASAP1 is important for the regulation of focal adhesion assembly and/or organization by influencing the mechanisms responsible for the recruitment and organization of selected focal adhesion proteins such as paxillin and FAK.


Mokko Lactone Attenuates Doxorubicin-Induced Hepatotoxicity in Rats: Emphasis on Sirt-1/FOXO1/NF-κB Axis.
Doxorubicin (DOX), a common chemotherapeutic agent, suffers serious adverse effects including hepatotoxicity. Mokko lactone (ML) is a guainolide sesquiterpene with promising biological activities. The study aimed to evaluate the protection offered by ML against hepatotoxicity induced by DOX in rats. Our data indicated ML exhibited protective effects as evidenced by ameliorating the rise in serum activities of alanine transaminase, aspartate transaminase and alkaline phosphatase. This was confirmed histologically as ML prevented DOX-induced pathological alteration in liver architecture. Further, ML administration significantly prevented malondialdehyde accumulation, glutathione depletion and superoxide dismutase and catalase exhaustion. Antioxidant action of ML was associated with enhanced expression of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and a lower expression of forkhead box protein O1 (FOXO1). Also, ML showed potent anti-inflammatory activities highlighted by decreased expression of interleukin 6, tumor necrosis factor α and nuclear factor κB (NF-κB). The anti-apoptotic effects of ML were associated with decreased Bax and enhanced Bcl-2 mRNA expression in liver tissues. ML caused a significant up-regulation in the expression of silent information regulator 1 (Sirt-1). Therefore, it can be concluded that ML prevents liver injury caused by DOX. This could partially be due to the ML regulatory activities on Sirt-1/FOXO1/NF-κB axis.


Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory.
Understanding the mechanisms of episodic memory requires linking behavioral data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action.


Efficient Flower Text Entry in Virtual Reality.
Text entry is a frequently used task in virtual reality (VR) applications, and controller is the most common interactive device in current VR systems. However, in terms of typing speed, there is still a gap between the existing controller-based text entry techniques and using a physical keyboard in reality, so it is important to improve the efficiency of the controller-based text entry. In this paper, we introduce Flower Text Entry, a single-controller text entry method based on a newly designed flower-shaped keyboard using hand 3D translation interaction for letters selection. We conduct user studies to optimize the keyboard design and the mapping between the interaction and selection, so as to evaluate our method. The results show that our method has high typing speed, lower error rate, and is very friendly to novices compared with the state-of-the-art controller-based text entry methods. After a short training, the novice group can type at 17.65 words per minute (WPM), and the potential expert group can type at 22.97 WPM. The highest typing speed is up to 30.80 WPM achieved by a potential expert participant.


Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020).
PRC2 is a histone methyltransferase complex associated with several cancer types. Tazemetostat was recently approved as the first inhibitor targeting the catalytic subunit EZH2 and several other EZH2 inhibitors are now under clinical evaluation. Beyond EZH2, researchers have also explored other approaches including PRC2 activators, dual agents inhibiting both EZH1 and EZH2, allosteric inhibitors binding to EED, and compounds which induce the degradation of PRC2 constituent proteins. This review provides an overview of anticancer therapies targeting PRC2 during the period 2016-2020 including clinical trials, patents and the scientific literature. The approval of tazemetostat marks the clinical validation of EZH2 for the treatment of cancer. Despite this success many questions remain; for instance, tazemetostat was briefly placed on clinical hold for safety concerns, while another EZH2 inhibitor (GSK126) demonstrated insufficient efficacy during a Phase I/II trial. It is important to understand these risks as PRC2 therapies progress through clinic evaluation. Alternative approaches to target PRC2 may offer distinct advantages over the inhibition of EZH2, including the potential to overcome EZH2 resistance mutations. However, these emerging modalities may also incur new challenges as they progress toward the clinic. Nonetheless, the diversity of agents under development represents a wealth of therapeutic options for future patients.


GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin's function.
Megalin is the most abundant endocytic receptor in the proximal tubule epithelium (PTE), where it is concentrated in clathrin-coated pits (CCPs) and vesicles in the brush border region. The heterotrimeric G protein alpha subunit, Galphai3, has also been localized to the brush border region of PTE. By immunofluorescence GIPC and GAIP, components of G protein-mediated signaling pathways, are also concentrated in the brush border region of PTE and are present in megalin-expressing cell lines. By cell fractionation, these signaling molecules cosediment with megalin in brush border and microvillar fractions. GAIP is found by immunoelectron microscopy in CCPs, and GIPC is found in CCPs and apical tubules of endocytic compartments in the renal brush border. In precipitation assays, GST-GIPC specifically binds megalin. The concentration of Galphai3, GIPC, and GAIP with megalin in endocytic compartments of the proximal tubule, where extensive endocytosis occurs, and the interaction between GIPC and the cytoplasmic tail of megalin suggest a model whereby G protein-mediated signaling may regulate megalin's endocytic function and/or trafficking.


Copper-catalyzed radical relay in C(sp3)-H functionalization.
Radical-involved transition metal (TM) catalysis has greatly enabled new reactivities in recent decades. Copper-catalyzed radical relay offers enormous potential in C(sp3)-H functionalization which combines the unique regioselectivity of hydrogen atom transfer (HAT) and the versatility of copper-catalyzed cross-coupling. More importantly, significant progress has been achieved in asymmetric C-H functionalization through judicious ligand design. This tutorial review will highlight the recent advances in this rapidly growing area, and we hope this survey will inspire future strategic developments for selective C(sp3)-H functionalization.


Unveiling the unfolding pathway of F5F8D disorder-associated D81H/V100D mutant of MCFD2 via multiple molecular dynamics simulations.
Combined factor deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in the LMAN1 or MCFD2 genes. It has been proposed that this pathogenic process occurs via a multi-step pathway involving metal loss, EF-hand-Ca21 dissociation and assembly of misfolded MCFD2-LMAN1 complex. Here, we have investigated the solution conformations of the MCFD2((D81H,V100D)) protein mutant through extensive molecular dynamics (MD) simulations. The V100D, one of the many MCFD2 mutations known to be associated to F5F8D, is difficult to be reconciled with the pathway model because it is located far from the metal sites and the MCFD2/LMAN1 interface. Consequently, an inspection of all the steps involved in D81H/V100D MCFD2 misfolding is expected to provide hints in the understanding of the molecular basis of the disease. A comparison with parallel studies carried out for the Wild-Type (WT) MCFD2 pointed out that the mutation decreases the affinity of the protein for the Ca21 ion. Multiple explicit solvents MD simulations (50 ns) performed on the two proteins revealed that in the WT protein, stable H-bond network and compact hydrophobic core region are created thus confirming a pivotal role of this region in driving the biophysical properties of the entire protein. In fact it is shown that the V100D mutation, although located far away the EF-hand domain, may induce subtle modification in the structural core of MCFD2 leading to the loosening of metal binding and to the formation of metastable intermediate states along the unfolding pathway. The native-like hydrophobic cluster formed near the V100 residue in the wild-type protein is disrupted by the negatively charged Asparagine residue. Furthermore, the presence of the D81H mutation in the EF-1 hand domain may also increase the protein unfolding rate and consequently prevent the formation of the MCFD2-LMAN1 complex. The detailed structural insights obtained from our large-scale simulations complement the clinical features and offer useful insights into the mechanism behind MCFD2 protein misfolding.


Apoptosis and microvessel density in gastric cancer: correlation with tumor stage and prognosis.
Gastric cancer remains one of the most common human malignancies with a poor prognosis. Apoptosis is known to be a programmed cell death and its inhibition is involved in the unregulated cellular growth that leads to neoplasms. Microvessel density (MVD) has been investigated as a promoting factor for angiogenesis with conflicting results about its relation to survival. The aim of our study was to search a correlation between these factors and some clinicopathological features and prognosis. Identification of apoptotic cells was performed applying the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and recorded as apoptotic index (A.I.), whereas monoclonal antibodies were used for the study of MVD. A significant correlation was found between low and high A.I. and the subgroup of patients in Stages I and II (P < 0.02); 20 per cent of patients with a low A.I. showed an overall survival longer than 5 years versus 44 per cent of patients with an high A.I. (P = 0.041). High MVD was significantly related to the T stage (P = 0.036) and to a poorer 5-year overall survival (P < 0.05). Further studies are required to confirm the role of apoptosis and MVD in the development and progression of gastric cancer.


The motility of Chara corallina myosin was inhibited reversibly by 2,3-butanedione monoxime (BDM).
We studied the effects of 2,3-butanedione monoxime (BDM) on the cytoplasmic streaming of Chara corallina and on the motility of myosin prepared from the same plant to examine whether this reagent really affects the plant class XI myosin. It was found that BDM inhibited both cytoplasmic streaming and the motility of myosin at a very similar concentration range (10-100 mM). BDM introduced directly into tonoplast-free cells also inhibited cytoplasmic streaming. These results suggested that effect of BDM on cytoplasmic streaming was exerted through myosin and not through ion channels at least in Chara corallina, though a very high concentration of BDM was required.


Pathway of Photosynthetic Malate Formation in Vitis vinifera, a C(3) Plant.
The time course of intramolecular isotope distribution in phosphoglyceric acid and serine was determined after exposure of grape leaf discs (Vitis vinifera L.) to (14)CO(2) (1000 microliters per liter) for variable metabolic periods, and the labeling patterns were compared with the respective isotope distribution in the C(1-3) fragment of malic acid. The results clearly support the classical concept of a close precursor-product relationship between photosynthetic phosphoglycerate and malic acid. Under the assimilatory conditions used in this study, there was no indication of an immediate carbon transfer from serine to malate as has been suggested for C(3) plants (Kent et al. 1974 Plant Physiol 53: 491-495) because of a coincident labeling of these compounds in Vicia faba. According to our data, previous evidence in favor of this hypothetical pathway is based largely on an unusual (14)C distribution in serine, due to an extreme suppression of photorespiration, as well as on arbitrary comparisons between compounds of divergent kinetic characteristics and consequently different degrees of metabolic label randomization.


Bolometric Effect in Bi2 O2 Se Photodetectors.
Bi2 O2 Se is emerging as a photosensitive functional material for optoelectronics, and its photodetection mechanism is mostly considered to be a photoconductive regime in previous reports. Here, the bolometric effect is discovered in Bi2 O2 Se photodetectors. The coexistence of photoconductive effect and bolometric effect is generally observed in multiwavelength photoresponse measurements and then confirmed with microscale local heating experiments. The unique photoresponse of Bi2 O2 Se photodetectors may arise from a change of hot electrons during temperature rises instead of photoexcited holes and electrons. Direct proof of the bolometric effect is achieved by real-time temperature tracking of Bi2 O2 Se photodetectors under time evolution after light excitation. Moreover, the Bi2 O2 Se bolometer shows a high temperature coefficient of resistance (-1.6% K-1 ), high bolometric coefficient (-31 nA K-1 ), and high bolometric responsivity (>320 A W-1 ). These findings offer a new approach to develop bolometric photodetectors based on Bi2 O2 Se layered materials.


Type A aortic dissection developed after type B dissection with the presentation of shoulder pain: A case report.
Aortic dissection (AD) is a life-threatening condition with a high mortality rate without immediate medical attention. Early diagnosis and appropriate treatment are critical in treating patients with AD. In the emergency department, patients with AD commonly present with classic symptoms of unanticipated severe chest or back pain. However, it is worth noting that atypical symptoms of AD are easily misdiagnosed. A 51-year-old woman was first diagnosed with scapulohumeral periarthritis due to left shoulder pain. After careful examination of her previous medical history and contrast-enhanced computed tomography angiography, the patient was diagnosed with a new type A AD after chronic type B dissection in the ascending aorta. The patient was successfully treated with surgical replacement of the dissected aortic arch and remains in good health. New retrograde type A AD after chronic type B dissection is relatively rare. It is worth noting that a physician who has a patient with suspected AD should be vigilant. Both patient medical history and imaging tests are crucial for a more precise diagnosis.


Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation.
The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).


Sulphone induced exfoliative dermatitis and hepatitis.
Exfoliative dermatitis associated with hepatitis has been reported in leprosy patients taking dapsone in daily dosage of 200 mg daily or more previously. This report concerns a 40 year-old-female who developed exfoliative dermatitis and hepatitis six weeks after starting dapsone in daily dosage of 100 mg for treatment of leprosy. She responded dramatically to administration of corticosteroids.


A phase I toxicity study of human rDNA interferon in patients with solid tumours.
This study was designed to evaluate the clinical tolerance to multiple IM injections of rDNA-produced human alpha-2 interferon (IFN) (Schering-Plough 30500) in patients with solid tumours. IFN was administered in escalating IM doses in separate groups of patients daily for 14 days and then twice weekly for a further 10 weeks. The dosage levels were 1, 3, 10, and 30 million U/injection. Subjective toxicity could be divided into two types, acute and chronic. The acute reactions took the form of an influenza-like syndrome consisting in chills, rigors, headache, tremor, nausea, vomiting, and myalgia. These symptoms were dose-related but tachyphylaxis developed with continued dosing. The chronic toxicity consisted of malaise, lethargy, fatigue, anorexia, and confusion. These symptoms were not so dose-dependent and tended to become more severe with prolonged treatment. Objective toxicity consisted of myelosuppression and liver dysfunction. Granulocyte counts below 1.0 X 10(9)/l were seen in three patients at the 30-million-U level, with platelet counts less than 100 X 10(9)/l in two of these. Elevation of the liver enzymes were seen in all five patients treated at 30 million U, but returned to normal after 1 week without IFN in all but one patient. A tolerable dose (IM) for phase II/III studies lies between 3 and 10 million U for daily scheduling and between 10 and 30 million U for twice-weekly injections.


PCNA and protein P53 in recurrent supratentorial glial brain tumors: studies on correlation between morphology and tumor progression.
Thirty seven cases of recurrent gliomas with survival time from 3 month to 13 years were investigated morphologically and immunohistochemically to evaluate progression and transformation of tumors. Using antibodies against PCNA and p53 the proportion of positively marked cells (nuclei) to all tumor cells was assessed at both primary and secondary surgery. This was compared with morphology and survival time between first and second surgery. In 10 cases (27.0%) there were no positively marked cells. In the remaining 27 cases (73.0% of the whole group), the following indices (percents of positive cells) were calculated: for patients with survival below 1 year (mean = 9m) 28.3% PCNA-positive cells and 30.3% p53-positive cells at first operation. For recidiving tumors both indices were lower namely for PCNA 20.9% and for protein p53-26.7%. For patients with survival over 1 year (mean = 4.8y) the index after I operation for PCNA was 25.5% and was higher than found after II operation-22.3%. In contrary, the index for protein p53 was 20.1% after I operation and was lower as compared with the index after II operation-28.2%. Eleven of twelve fibrillary astrocytomas and all five gemistocytic astrocytomas at first operation underwent changes towards malignisation. The immunocytochemical results confirm the high phenotypic differentiation what is reflected in different indices for PCNA and p53 of tumors.


Tuberculoma of the cheek: a case report.
Tuberculoma of the cheek in the absence of tuberculosis elsewhere in the body is rarely seen and hence rarely thought of as a differential diagnosis when such a patient presents. In the following case, the patient was provisionally diagnosed as carcinoma of the cheek because of the exophytic nature of the growth and its presentation. However, histopathology of a biopsy revealed tuberculoma and the response to antituberculous therapy was rapid and curative.


Seroepidemiology of Helicobacter pylori infection in Guadeloupe.
854 sera collected from blood donors in Guadeloupe were screened for Helicobacter pylori immunoglobulin G antibodies by a commercial enzyme-linked immunosorbent assay kit. The overall prevalence was 55.2%; it increased significantly with age from 36.1% at 18-19 years to 63.7% at 50-59 years (P = 0.003).


On-line microdialysis sample cleanup for electrospray ionization mass spectrometry of nucleic acid samples.
A major limitation of electrospray ionization mass spectrometry (ESI-MS) for oligonucleotide analysis arises due to sodium adduction, a problem that increases with molecular weight. Sodium adduction can preclude useful measurements when limited sample sizes prevent off-line cleanup. A novel and generally useful on-line microdialysis technique is described for the rapid (approximately 1-5 min) DNA sample cleanup for ESI-MS. Mass spectra of oligonucleotides of different size and sequence showing no significant sodium adduct peaks were obtained using the on-line microdialysis system with sodium chloride concentrations as high as 250 mM. Signal-to-noise ratios were also greatly enhanced compared to direct infusion of the original samples. By using ammonium acetate as the dialysis buffer, it was also found that the noncovalent association of double-stranded oligonucleotides could be preserved during the microdialysis process, allowing analysis by ESI-MS.


Heterometallic Werner complexes as energetic materials.
New heterometallic Werner complexes have been synthesized by combining the cobalt cationic [Co(NH3)6]3+ species with a nitrato metal fragment [M(NO3)4](x-) (M = Fe, Mn, Cu, Zn) or with metal oxides X2MO4 (M = Mo, W and X = Na, NH4). Depending on the metals, an organic and/or a water synthetic route was developed. X-Ray data on Mn and Cu precursors have shown the versatility of nitrate ligand coordination. TDA-TGA studies have been performed to demonstrate the energetic material character. The [Co(NH3)6]x[M(NO3)4]3 complexes display a good oxygen balance and, as shown by standard sensitivity tests, are suitable for automotive applications.


Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance.
The ATP-dependent glutathione S-conjugate export pump (GS-X pump) has been suggested to play a role in the mechanism of cisplatin resistance. The purpose of this study was to determine the relationship between intracellular glutathione (GSH) levels and GS-X pump activity and whether GS-X pump overexpression results in cisplatin resistance. We transfected the human gamma-glutamylcysteine synthetase (gamma-GCS) gene into a human small-cell lung cancer cell line, SBC-3, producing SBC-3/GCS. The intracellular GSH content of SBC-3/GCS was twice that of the parental line, its GS-X pump activity was significantly enhanced and cellular cisplatin accumulation decreased. SBC-3/GCS showed higher resistance (relative resistance value of 7.4) to cisplatin than the parental line SBC-3. These data indicate that gamma-GCS gene overexpression induces cellular cisplatin resistance associated with increases in both the GSH content and GS-X pump activity, resulting in reduced cisplatin accumulation. In conclusion, GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance.


BJBN: BERT-JOIN-BiLSTM Networks for Medical Auxiliary Diagnostic.
This study proposed a medicine auxiliary diagnosis model based on neural network. The model combines a bidirectional long short-term memory(Bi-LSTM)network and bidirectional encoder representations from transformers (BERT), which can well complete the extraction of local features of Chinese medicine texts. BERT can learn the global information of the text, so use BERT to get the global representation of medical text and then use Bi-LSTM to extract local features. We conducted a large number of comparative experiments on datasets. The results show that the proposed model has significant advantages over the state-of-the-art baseline model. The accuracy of the proposed model is 0.75.


Genetic influence on the working memory circuitry: behavior, structure, function and extensions to illness.
Working memory is a highly heritable complex cognitive trait that is critical for a number of higher-level functions. However, the neural substrates of this behavioral phenotype are intricate and it is unknown through what precise biological mechanism variation in working memory is transmitted. In this review we explore different functional and structural components of the working memory circuitry, and the degree to which each of them is contributed to by genetic factors. Specifically, we consider dopaminergic function, glutamatergic function, white matter integrity and gray matter structure all of which provide potential mechanisms for the inheritance of working memory deficits. In addition to discussing the overall heritability of these measures we also address specific genes that may play a role. Each of these heritable components has the potential to uniquely contribute to the working memory deficits observed in genetic disorders, including 22q deletion syndrome, fragile X syndrome, phenylketonuria (PKU), and schizophrenia. By observing the individual contributions of disruptions in different components of the working memory circuitry to behavioral performance, we highlight the concept that there may be many routes to a working memory deficit; even though the same cognitive measure may be a valid endophenotype across different disorders, the underlying cause of, and treatment for, the deficit may differ. This has implications for our understanding of the transmission of working memory deficits in both healthy and disordered populations.


Clinical research in home care. A report of affiliates of the Visiting Nurse Associations of America.
Home care providers rarely initiate research because of limited resources and the perception that research belongs to academic institutions. A survey of the affiliates of the Visiting Nurse Associations of America identified the types of research activities performed and the interest level of nurses in participating in research activities.


The complex contribution of sociodemographics to decision-making power in gay male couples.
Relationship power is an important dyadic construct in close relationships that is associated with relationship health and partner's individual health. Understanding what predicts power in heterosexual couples has proven difficult, and even less is known about gay couples. Resource models of power posit that demographic characteristics associated with social status (e.g., age, income) confer power within the relationship, which in turn shapes relationship outcomes. We tested this model in a sample of gay male couples (N = 566 couples) and extended it by examining race and HIV status. Multilevel modeling was used to test associations between demographic bases of power and decision-making power. We also examined relative associations among demographic bases and decision-making power with relationship satisfaction given the literature on power imbalances and overall relationship functioning. Results showed that individual income was positively associated with decision-making power, as was participant's HIV status, with HIV-positive men reporting greater power. Age differences within the relationship interacted with relationship length to predict decision-making power, but not satisfaction. HIV-concordant positive couples were less satisfied than concordant negative couples. Higher power partners were less satisfied than lower power partners. Demographic factors contributing to decision-making power among same-sex male couples appear to share some similarities with heterosexual couples (e.g., income is associated with power) and have unique features (e.g., HIV status influences power). However, these same demographics did not reliably predict relationship satisfaction in the manner that existing power theories suggest. Findings indicate important considerations for theories of power among same-sex male couples. (PsycINFO Database Record


Effect of thermally treated barley dietary fiber against hypercholesterolemia.
Dietary fiber is a nondigestible constituent of vegetal foods, formed by insoluble and soluble dietary fiber. The intake of dietary fiber, especially soluble dietary fiber, is limited and demands researcher's attention. The modification of cereal's dietary fiber, predominantly insoluble fiber, could be one possible solution. The current study evaluated the comparative effects of several thermal treatments on the modification of insoluble dietary fiber in barley and explored their therapeutic potential in vivo against hypercholesterolemia. The two cultivars of barley, Haider-93 and Jau-87, were thermally treated using different techniques, and dietary fiber was extracted. Successively, the intake of these dietary fibers was evaluated for its antilipidemic activity in normal and hypercholesterolemic rats. In the first phase, thermal treatments especially cooking without soaking increased the soluble fiber (68.08%). The roasting all increased the soluble fiber contents, however, at relatively lower rate (53.91%). The results of efficacy study revealed that biochemical parameters in control animals were within the normal clinical ranges, thus appraising the safe status of the experimental diets. The thermally treated barley fiber decreased total cholesterol (12.14%-12.63%), low-density lipoprotein (14.12%-14.85%), and triglycerides (2.25%-4.32%). The study recorded increasing trends for high-density lipoprotein in both normal and hypercholesterolemic rats. In the nutshell, thermal modification of dietary fiber increased the ratio of soluble to insoluble dietary fiber that improved its hypocholesterolemic potential. The thermally treated barley dietary fiber is effective in reducing the lipid profile in Sprague-dawley rats than untreated dietary fiber and, therefore, can be considered as a functional food and ingredient to cope different lifestyle diseases.


Integrated Management Strategies Increase Cottonseed, Oil and Protein Production: The Key Role of Carbohydrate Metabolism.
Cottonseed, oil, and protein, as the by-products of cotton production, have the potential to provide commodities to meet the increasing demand of renewable bio-fuels and ruminant feed. An increase in crop yield per unit area requires high-yielding cultivar management with an economic nitrogen (N) rate, an optimal N application schedule, high-yielding plant populations and strong seedlings. Whether the integration of these agronomic practices into a coherent management system can increase the productivity of cotton fiber, embryo oil and protein requires experimental elucidation. In this 2-year study, conventional management practices (CM) were used as a control, and two integrated management strategies (IMS1 and IMS2) were considered at two soil fertility levels (high soil fertility and low soil fertility) to analyze the metabolic and biochemical traits of cotton embryos. The results illustrate that the cottonseed, oil, and protein yields for IMS1 and IMS2 were significantly higher than those under CM at both soil fertility levels and the fiber yield increased as well. The IMS regulated the maternal photo thermal environment by delaying the flowering date, resulting in increases in the seed weight. In developing cotton embryos, the IMS increased the embryo weight accumulation rate and biomass partitioning into oil and protein, which were associated with high activities of H+-ATPase, H+-PPase, sucrose synthase (SuSy), and cell wall invertase (C-INV) and low activities of sucrose phosphate synthase (SPS) and vacuole invertase (V-INV). Increased hexoses (D-fructose, D-glucose) content contributed to the oil and protein contents. These results suggest that increased sucrose/H+ symport, sucrose hydrolysis, hexoses synthesis, and cumulative photo-thermal product (PTP), especially in the early stage of embryo growth, play a dominant role in the high productivity of cotton oil and protein.


Phosphorylation of calcium adenosinetriphosphatase by inorganic phosphate: reversible inhibition at high magnesium ion concentrations.
Magnesium stimulates phosphorylation of the calcium pump protein of the sarcoplasmic reticulum by inorganic phosphate, but the effect is reversed by high [Mg2+]. This reversal is readily explained in terms of the generally accepted existence of two conformational states of the enzyme, E1 and E2. E2 is the form of the enzyme that can be phosphorylated by Pi, and it has one binding site for Mg2+. E1 is the form of the enzyme that has two high-affinity Ca2+ binding sites, and it is phosphorylated by ATP when Ca2+ is bound. Mg2+ can bind weakly to the two Ca2+ sites and to a third site known to be present on E1; this stabilizes E1 at the expense of E2 when [Mg2+] is large. Stabilization of E1 at pH 6.2 and 25 degrees C was found to be a highly cooperative function of [Mg2+] and was not prevented by increasing [Pi]. The latter result requires the existence of a binding site for Pi on E1, with an affinity for Pi comparable to that of E2. Cooperativity with respect to [Mg2+] requires that E2 is the stable state of the enzyme in the absence of ligands, with an equilibrium constant [E2]/[E1] on the order of 10(3) or higher at pH 6.2 and 25 degrees C.


Stochastic resonance of ensemble neurons for transient spike trains: wavelet analysis.
By using the wavelet transformation (WT), I have analyzed the response of an ensemble of N (=1, 10, 100, and 500) Hodgkin-Huxley neurons to transient M-pulse spike trains (M=1 to 3) with independent Gaussian noises. The cross correlation between the input and output signals is expressed in terms of the WT expansion coefficients. The signal-to-noise ratio (SNR) is evaluated by using the denoising method within the WT, by which the noise contribution is extracted from the output signals. Although the response of a single (N=1) neuron to subthreshold transient signals with noises is quite unreliable, the transmission fidelity assessed by the cross correlation and SNR is shown to be much improved by increasing the value of N: a population of neurons plays an indispensable role in the stochastic resonance (SR) for transient spike inputs. It is also shown that in a large-scale ensemble, the transmission fidelity for suprathreshold transient spikes is not significantly degraded by a weak noise which is responsible to SR for subthreshold inputs.


Effects of commune-internal migration in Finland on the spatial distribution of population and on dwelling house utilization.
"The article is based on a programme of research which has been pursued for some years with the purpose of describing the extent and spatial orientation of commune-internal migration [in Finland], a topic about which very little has previously been known, relating this form of migration to total population movement and to dwelling house requirements and utilization. The analysis yields information on the dynamics of population changes occurring in areas on the margins of permanent settlement, while at the same time taking into consideration the effects of regional and in particular housing policy decisions upon the spatial distribution of population."


Elbasvir and grazoprevir for chronic hepatitis C genotypes 1 and 4.
During the last few years, treatment of hepatitis C virus (HCV) revolutionized with the appearance of direct antiviral agents especially for patients with HCV genotypes 1 and 4 infections. Elbasvir (NS5A inhibitor) and grazoprevir (NS3/4A protease inhibitor) are newly developed drugs that are presented in fixed dose combination tablets. Areas covered: This review covers the mechanism of action, pharmacokinetic and pharmacodynamics properties, clinical uses, safety and efficacy of elbasvir/grazoprevir in managing a wide variety of easy and difficult to treat populations (such as presence of cirrhosis, treatment experienced, co-infection with HIV and patients with inherited blood disorders). Expert commentary: Elbasvir/grazoprevir combination showed great efficacy with high rates of sustained virological response rates in genotypes 1 and 4 HCV infection. In addition, it retained a good safety profile and is generally well tolerated.


The Activated Macrophage - A Tough Fortress for Virus Invasion: How Viruses Strike Back.
Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.


Effects of a single dose of orally-administered spermine on the intestinal development of unweaned rats.
Investigations were undertaken to obtain information on the mechanism by which orally administered spermine induces postnatal maturation in the rat intestine. Suckling rats ingested one dose of spermine (8 mumol) then were sacrificed at different intervals. -A. Proximal and distal parts of the intestine were homogenised. -B. A modification of the Wieser's technique was used to isolate cell fractions from the proximal mucosa. Wet weight and length of intestine; protein content, DNA amount, disaccharidase activity, polyamine amounts in intestinal and cellular extracts were measured. Spermine ingestion induced two phases of events: first, a cellular desquamation then a new cell differentiation. In the isolated epithelial cells, two and four hours after spermine ingestion, modifications in lactase and maltase specific activity were recorded, as were variations in spermine, spermidine and putrescine content. These observations clarify the cellular and molecular events of the intestinal development occurring after spermine ingestion and open new research perspectives.


Management of COVID-19 in an Outpatient Dialysis Program.
In March 2020, the COVID-19 pandemic became an increasingly urgent issue of public health concern in the United States. Patients on dialysis are considered to be at increased risk for infection due to their medical comorbidities and need for continued face-to-face encounters in dialysis units. In our outpatient dialysis practice, 42 out of 269 patients (15.6%) were infected with COVID-19 during the first wave of the pandemic. In this retrospective report, we review issues of infection control, access to interventional procedures, and communication encountered in our practice. We discuss lessons learned in patient outcomes and the importance of transitioning patients to home modalities. Further planning for a potential second wave of COVID-19 may help ensure improved quality of care for patients in the dialysis program.


Genetic markers applied in regression tree prediction models.
Classification and regression tree (CART) modelling was used to determine infectious hypodermal and haematopoietic necrosis virus (IHHNV) resistance and susceptibility in Penaeus stylirostris. In a previous study, eight random amplified polymorphic DNA (RAPD) markers and viral load values using real-time quantitative PCR were obtained and used as the training data set in order to create numerous regression tree models. Specifically, the genetic markers were used as categorical predictor variables and viral load values as the dependent response variable. To determine which model has the highest predictive accuracy for future samples, RAPD fingerprint data was generated from new Penaues stylirostris IHHNV resistant and susceptible individuals and used to test the regression models. The best performing tree was a four terminal node tree with three genetic markers as significant variables. Marker-assisted breeding practices may benefit from the creation of regression tree models that apply genetic markers as predictive factors. To our knowledge this is the first study to use RAPD markers as predictors within a CART prediction model to determine viral susceptibility.


The Longitudinal Contribution of Early Morphological Awareness Skills to Reading Fluency and Comprehension in Greek.
The purpose of this longitudinal study was to examine the role of three morphological awareness (MA) skills (inflection, derivation, and compounding) in word reading fluency and reading comprehension in a relatively transparent orthography (Greek). Two hundred and fifteen (104 girls; Mage = 67.40 months, at kindergarten) Greek children were followed from kindergarten (K) to grade 2 (G2). In K and grade 1 (G1), they were tested on measures of MA (two inflectional, two derivational, and three compounding), letter knowledge, phonological awareness, rapid automatized naming (RAN), and general cognitive ability (vocabulary and non-verbal IQ). At the end of G1 and G2, they were also tested on word reading fluency and reading comprehension. The results of hierarchical regression analyses showed that the inflectional and derivational aspects of MA in K as well as all aspects of MA in G1 accounted for 2-5% of unique variance in reading comprehension. None of the MA skills predicted word reading fluency, after controlling for the effects of vocabulary and RAN. These findings suggest that the MA skills, even when assessed as early as in kindergarten, play a significant role in reading comprehension development.


Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers.
Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis.


Influence of Coastal Upwelling on SST Trends along the South Coast of Java.
The south coast of Java has warmed at a much lower rate than adjacent ocean locations over the last three decades (1982-2015). This behavior can be observed during the upwelling season (July-October) and it is especially patent in August and September when upwelling attains the highest values. Although different warming rates (ocean-coast) had been previously observed in other areas around the world, this behavior was always linked to situations where upwelling increased or remained unchanged. South Java warming is observed at ocean locations and cooling near shore but under a scenario of decreasing upwelling (~30% in some cases). The origin of coastal cooling is due to changes in the vertical structure of the water column. A vein of subsurface water, which has cooled at a rate higher than 0.3°C per decade, is observed to enter from the northwestern part of the study area following the South Java Current. This water only manifests at surface near coast, where it is pumped up by coastal upwelling.


Genomic Insights Into the Lifestyles of Thaumarchaeota Inside Sponges.
Sponges are among the oldest metazoans and their success is partly due to their abundant and diverse microbial symbionts. They are one of the few animals that have Thaumarchaeota symbionts. Here we compare genomes of 11 Thaumarchaeota sponge symbionts, including three new genomes, to free-living ones. Like their free-living counterparts, sponge-associated Thaumarchaeota can oxidize ammonia, fix carbon, and produce several vitamins. Adaptions to life inside the sponge host include enrichment in transposases, toxin-antitoxin systems and restriction modifications systems, enrichments previously reported also from bacterial sponge symbionts. Most thaumarchaeal sponge symbionts lost the ability to synthesize rhamnose, which likely alters their cell surface and allows them to evade digestion by the host. All but one archaeal sponge symbiont encoded a high-affinity, branched-chain amino acid transporter system that was absent from the analyzed free-living thaumarchaeota suggesting a mixotrophic lifestyle for the sponge symbionts. Most of the other unique features found in sponge-associated Thaumarchaeota, were limited to only a few specific symbionts. These features included the presence of exopolyphosphatases and a glycine cleavage system found in the novel genomes. Thaumarchaeota have thus likely highly specific interactions with their sponge host, which is supported by the limited number of host sponge species to which each of these symbionts is restricted.


Ground fused silica processed by combined chemical etching and CO2 laser polishing with super-smooth surface and high damage resistance.
Laser damage in fused silica, particularly ultraviolet laser damage, is still a key problem limiting the development of high-power laser systems. In this Letter, a combined process of chemical etching and CO2 laser polishing was applied to ground fused silica. A super-smooth surface with a root-mean-square roughness of 0.25 nm was achieved through this combined process. Furthermore, the combined process can reduce the introduction of photoactive metal impurity elements, destructive defects, and chemical-structure defects, resulting in a 0% probability damage threshold nearly 33% higher than a conventional chemical mechanical polished sample for a 7.6 ns pulse at a wavelength of 355 nm.


A hybrid outer membrane protein antigen for vaccination against Pseudomonas aeruginosa.
Recently a hybrid protein containing parts of the outer membrane proteins OprF (aa 190-342) and OprI (aa 21-83) from Pseudomonas aeruginosa fused to the glutathione-S-transferase was shown to protect mice against a 975-fold 50% lethal dose of P. aeruginosa. To omit the use of the GST-protein, the hybrid protein OprF-OprI was expressed in E. coli using distinct modifications which have not to be eliminated after its expression. Using different signal peptides, the yield of the hybrid protein OprF-OprI in E. coli could be increased to 30% of the total cell protein, however, only a very small amount of the hybrid preprotein was processed and could be isolated from the periplasm of the host. A construct containing an N-terminal extension of 11 amino acids from the original OprF gene gave rise to a significantly higher expression in the cytoplasm. Purification was facilitated by the addition of a five histidine tag at the C-terminus. An even higher expression was obtained by a construct in which a six histidine tag was attached to the N-terminus of the hybrid protein. The N-terminal extended OprF-OprI as well as the N-terminal his-tagged OprF-OprI hybrid antigens were purified by immobilized-metal affinity chromatography under native and denaturing conditions and can now be tested for protectivity against P. aeruginosa in animal model systems.


[A case of uncomplicated retinal astrocytoma].
A 45-year-old Japanese women whose left eye contained an elevated, whitish yellow, and multi-lobed mass of 1.5 disc diameters that extended out from the retina adjacent to the optic disc. Ultrasonography demonstrated high reflectivity corresponding to the lesion of the left eye. By fluorecein angiography the tumor showed autofluorescein, retinal vessel through the tumor in the venous phase, and in the late phase pronounced staining of the tumor. A scanning laser ophthalmoscope showed the surface in detail. A search of the literature revealed only 16 cases of uncomplicated retinal astrocytoma.


Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease.
Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence. We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence. Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months. We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.


InDependent Diabetes Trust.
The InDependent Diabetes Trust is a UK-based charity run by people with diabetes for others living with the condition. It was set up in 1994 as the Insulin Dependent Diabetes Trust (IDDT), a registered charity. It is run entirely by voluntary donations and does not accept funding from pharmaceutical companies.


Responding to challenges in modern combat casualty care: innovative use of advanced regional anesthesia.
The war in Iraq has resulted in a high incidence of severe extremity injury requiring multiple surgical procedures and extensive rehabilitation. We describe the use of advanced regional anesthesia to meet this significant medical challenge. From March 2003 to December 2004, 4,100 casualties have been evacuated to Walter Reed Army Medical Center (WRAMC). Of 1,400 inpatients, 750 have been battle-injured with 500 having extremity injuries. Of these, 287 (57%) received surgical care incorporating regional anesthesia including single-injection peripheral nerve blocks and continuous peripheral and epidural infusion catheters. Wounding, surgical, anesthetic, and outcomes data have been prospectively collected. Over 900 operations (mean 4+/-2/patient) were performed on 287 casualties prior to arrival at WRAMC, and 634 operations (mean 2+/-1/patient) were performed at WRAMC. Thirty-five percent of this cohort was amputees. In the study group, 646 advanced regional anesthesia procedures, including 361 continuous peripheral nerve blocks (CPNBs), were performed with a mean catheter infusion time of 9 days (1-34). Catheter-related complications occurred in 11.9% of casualties and were technical or minor in nature. Catheter-related infection rate was 1.9%. In 126 casualties with indwelling CPNB catheters, a significant decrease in pain score over 7 days was apparent (mean 3.7+/-0.2 to 2.2+/-0.2, P<0.001). Advanced regional anesthetic techniques allowed for safe perioperative surgical anesthesia and analgesia in the management of the modern combat casualty.


Pan-cancer analysis: SPAG5 is an immunological and prognostic biomarker for multiple cancers.
Sperm-associated antigen 5 (SPAG5) is a mitotic spindle protein that regulates the separation of sister chromatids into daughter cells. Recent studies have discovered its overexpression in various cancers, suggesting its oncogenic characteristics and functions. However, a comprehensive analysis of SPAG5 regarding its diagnostic, prognostic, and immune-related effects across different cancer types is lacking. In this study, we employed bioinformatics methods and integrated multiple public databases to explore the potential oncogenic role of SPAG5. We analyzed its expression, prognosis, related chemicals, enriched pathways, immune infiltration, and its impact on different tumor genetic alterations. The results revealed that SPAG5 is highly expressed in most cancers and significantly correlates with poor patient prognosis. Additionally, SPAG5 expression showed potential for early cancer diagnosis in 15 different cancer types. In terms of tumor immunity, high expression of SPAG5 was associated with an immunosuppressive tumor microenvironment and immune therapy efficacy indicators. SPAG5 expression exhibited a negative correlation with most immune cell infiltrates but demonstrated a significant positive correlation with Th2 cells and MDSC cells. Multicolor fluorescence immunohistochemistry demonstrated that SPAG5 activates immune cell populations within tumors, indicating its significant role in the tumor microenvironment. Enrichment analysis indicated that SPAG5-related genes are mainly involved in cell cycle, cellular senescence, P53 signaling pathway, and FoxO signaling pathway. Furthermore, we confirmed the high expression of SPAG5 in cancer cells and observed that its knockdown upregulated the expression of the p53 protein. In conclusion, SPAG5 holds value as a diagnostic, prognostic, and immune biomarker in various cancers and may provide a novel target for tumor immunotherapy.


On the origin of the temperature dependence of the supercoiling free energy.
Monte Carlo simulations using temperature-invariant torsional and bending rigidities fail to predict the rather steep decline of the experimental supercoiling free energy with increasing temperature, and consequently fail to predict the correct sign and magnitude of the supercoiling entropy. To illustrate this problem, values of the twist energy parameter (E(T)), which governs the supercoiling free energy, were simulated using temperature-invariant torsion and bending potentials and compared to experimental data on pBR322 over a range of temperatures. The slope, -dE(T)/dT, of the simulated values is also compared to the slope derived from previous calorimetric data. The possibility that the discrepancies arise from some hitherto undetected temperature dependence of the torsional rigidity was investigated. The torsion elastic constant of an 1876-bp restriction fragment of pBR322 was measured by time-resolved fluorescence polarization anisotropy of intercalated ethidium over the range 278-323 K, and found to decline substantially over that interval. Simulations of a 4349-bp model DNA were performed using these measured temperature-dependent torsional rigidities. The slope, -dE(T)/dT, of the simulated data agrees satisfactorily with the slope derived from previous calorimetric measurements, but still lies substantially below that of Duguet's data. Models that involve an equilibrium between different secondary structure states with different intrinsic twists and torsion constants provide the most likely explanation for the variation of the torsion constant with T and other pertinent observations.


An update on chemotherapy of colorectal liver metastases.
Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy significantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.


Separation and identification of phenolic compounds of extra virgin olive oil from Olea europaea L. by HPLC-DAD-SPE-NMR/MS. Identification of a new diastereoisomer of the aldehydic form of oleuropein aglycone.
The phenolic fraction of a monovarietal extra virgin olive oil (EVOO) from Olea europaea L. var. Cornezuelo was studied by the hyphenated HPLC-DAD-SPE-NMR/MS techniques. This survey led to the identification of 25 main compounds. One was identified as a new diastereoisomer of the aldehydic form of oleuropein aglycone (AOA) and characterized by 1D and 2D NMR techniques. The relative configuration of this new AOA was determined as 5R*,8S*,9S* on the basis of the results obtained from the combination of NOE experiments and Monte Carlo conformational search calculations. Assuming, as for the described diastereoisomers, that the new AOA comes from the natural oleuropein aglycone (OA), the absolute configuration was proposed as 5S,8R,9R.


Carbonic Anhydrase-Deficient Mutant of Chlamydomonas reinhardii Requires Elevated Carbon Dioxide Concentration for Photoautotrophic Growth.
A mendelian mutant of the unicellular green alga Chlamydomonas reinhardii has been isolated which is deficient in carbonic anhydrase (EC 220.127.116.11) activity. This mutant strain, designated ca-1-12-1C (gene locus ca-1), was selected on the basis of a high CO(2) requirement for photoautotrophic growth. Photosynthesis by the mutant at atmospheric CO(2) concentration was very much reduced compared to wild type and, unlike wild type, was strongly inhibited by O(2). In contrast to a CO(2) compensation concentration of near zero in wild type at all O(2) concentrations examined, the mutant exhibited a high, O(2)-stimulated CO(2) compensation concentration. Evidence of photorespiratory activity in the mutant but not in wild type was obtained from the analysis of photosynthetic products in the presence of (14)CO(2). At air levels of CO(2) and O(2), the mutant synthesized large amounts of glycolate, while little glycolate was synthesized by wild type under identical conditions. Both mutant and wild type strains formed only small amounts of glycolate at saturating CO(2) concentration. At ambient CO(2), wild type accumulated inorganic carbon to a concentration several-fold higher than that in the suspension medium. The mutant cells accumulated inorganic carbon internally to a concentration 6-fold greater than found in wild type, yet photosynthesis was CO(2) limited. The mutant phenotype was mimicked by wild type cells treated with ethoxyzolamide, an inhibitor of carbonic anhydrase activity. These observations indicate a requirement for carbonic anhydrase-catalyzed dehydration of bicarbonate in maintaining high internal CO(2) concentrations and high photosynthesis rates. Thus, in wild type cells, carbonic anhydrase rapidly converts the bicarbonate taken up to CO(2), creating a high internal CO(2) concentration which stimulates photosynthesis and suppresses photorespiration. In mutant cells, bicarbonate is taken up rapidly but, because of a carbonic anhydrase deficiency, is not dehydrated at a rate sufficiently rapid to maintain a high internal CO(2) concentration.


Sub-etioplast localization of the enzyme NADPH: protochlorophyllide oxidoreductase.
The membranes from oat etioplasts have been separated by sucrose density gradient centrifugation into a heavy fraction of density 1.20 mg/ml (prolamellar body fraction) and a light fraction of density 1.12 mg/ml (prothylakoid fraction). The light fraction was shown to be enriched in protein, protochlorophyllide and the chloroplast enzyme CF1-ATPase, but to be deficient in saponins. In the electron microscope this fraction appeared as swollen vesicles. In contrast the heavy fraction appeared considerably enriched in crystalline, tubular material and was on analysis found to contain most of the etioplasts' saponin but with reduced protein and pigment. In the same experiments the enzyme NADPH: protochlorophyllide oxidoreductase showed the same distribution pattern as the CF1-ATPase suggesting its location on the prothylakoids.


Identifying Fenton-Reacted Trimethoprim Transformation Products Using Differential Mobility Spectrometry.
A transformation product of trimethoprim, a contaminant of emerging concern in the environment, is generated using an electro-assisted Fenton reaction and analyzed using differential mobility spectrometry (DMS) in combination with MS/MS techniques and quantum chemical calculations to develop a rapid method for identification. DMS is used as a prefilter to separate positional isomers prior to subsequent identification by mass spectrometric analyses. Collision induced dissociation of each DMS separated species is used to reveal fragmentation patterns that can be correlated to specific isomer structures. Analysis of the experimental data and supporting quantum chemical calculations show that methylene-hydroxylated and methoxy-containing phenyl ring hydroxylated transformation products are observed. The proposed methodology outlines a high-throughput technique to determine transformation products of small molecules accurately, in a short time and requiring minimal sample concentrations (<25 ng/mL).


A quantitative ranking of the Biomedical Informatics serials.
We have developed a quantitative serial ranking system based on multiple citation analysis techniques, library use statistics, expert opinion, and selected distinguishing publication characteristics. Evaluation criteria categories include: average Science Citation Index (Impact Factor, Immediacy Index, Total citations) rankings from 1987 to 1992; citation source counts of multiple "core" biomedical informatics publications; a questionnaire sent to American College of Medical Informatics Fellows; publication delay; distinguishing characteristics (e.g., subscription cost, total circulation, year established, places indexed, affiliation with a professional society, major biomedical resource library holdings); and the total number of interlibrary loan requests to the U. S. National Library of Medicine. The top serials were Computers and Biomedical Research, MD Computing, Methods of Information in Medicine, Medical Decision Making and Computers in Biology and Medicine.


[A model for analyzing ascending genealogies].
"This paper presents a model of ascending genealogies, with the definition and investigation of the functions allowing for the study of these genealogies as well as with the main algorithms used in operationalizing the model on a micro-computer. Examples of the type of results one may obtain with this model are provided; they concern file outputs as well as the computation of consanguinity and completeness coefficients." The examples provided concern the island of Saint Barthelemy, Guadeloupe. (SUMMARY IN ENG AND SPA)


Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-alpha: differential responses in keratinocytes and endothelial cells.
Thrombomodulin is a cell-surface anticoagulant glycoprotein expressed by vascular endothelial cells and epidermal keratinocytes. Thrombomodulin expression in endothelial cells is regulated by retinoic acid and tumor necrosis factor-alpha (TNF), agents that also modulate epidermal differentiation. We examined thrombomodulin function and regulation of thrombomodulin expression by all-trans retinoic acid (ATRA) and TNF in human keratinocytes and endothelial cells. Untreated keratinocytes and endothelial cells expressed thrombomodulin of comparable activity and apparent thrombin affinity. Incubation of keratinocytes with 10 mumol/L ATRA for 24 hours increased thrombomodulin activity 5.4 +/- 0.9-fold (mean +/- SE), with equivalent increases observed in thrombomodulin protein (5.5 +/- 2.1-fold) and mRNA (4.2 +/- 1.2-fold). Incubation of keratinocytes with 1.0 nmol/L TNF markedly increased expression of keratinocyte transglutaminase, but had no effect on thrombomodulin activity, protein, or mRNA. In endothelial cells, ATRA produced a small increase in thrombomodulin activity (1.9 +/- 0.1-fold), and incubation with TNF for 24 hours decreased thrombomodulin activity 83% +/- 7%. The activity profile of keratinocyte thrombomodulin exhibited a distinct maximum near 1.0 mmol/L Ca2+. These results demonstrate that keratinocyte thrombomodulin is regulated by retinoids and Ca2+, but not by TNF, and that regulation of thrombomodulin expression differs in keratinocytes and endothelial cells.


Supporting emotional health and wellbeing: the Solihull Approach.
The quality of early relationships is an important factor in the development of emotional health and wellbeing. Yet in the UK, we do not integrate support for the relationship between the baby and parents into antenatal parentcraft. Neither do we provide enough focus on the relationship in basic and post-qualification training or support for practitioners to integrate working with the relationship into their practice. The Solihull Approach provides one model for working with the relationship between parents and the child and between the parents and practitioner. It integrates concepts from disparate academic fields that can focus a practitioner's work on supporting the relationship between parents and baby or child, whether individually or in a parenting group.


The evolution of the surgical treatment of chronic pancreatitis.
To establish the current status of surgical therapy for chronic pancreatitis, recent published reports are examined in the context of the historical advances in the field. The basis for decompression (drainage), denervation, and resection strategies for the treatment of pain caused by chronic pancreatitis is reviewed. These divergent approaches have finally coalesced as the head of the pancreas has become apparent as the nidus of chronic inflammation. The recent developments in surgical methods to treat the complications of chronic pancreatitis and the results of recent prospective randomized trials of operative approaches were reviewed to establish the current best practices. Local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreaticoduodenectomy, with lowered morbidity and mortality. Local resection or excavation of the pancreatic head offers the advantage of lowest cost and morbidity and early prevention of postoperative diabetes. The late incidences of recurrent pain, diabetes, and exocrine insufficiency are equivalent for all 3 surgical approaches. Local resection of the pancreatic head appears to offer best outcomes and lowest risk for the management of the pain of chronic pancreatitis.


Manganese oxide nanomaterials for bacterial infection detection and therapy.
Bacterial infection has received substantial attention and poses a serious threat to human health. Although antibiotics can effectively fight against bacterial infection, the occurrence of antibiotic resistance has become increasingly serious in recent years, which tremendously hinders its clinical application. Consequently, it is urgent to explore novel strategies to achieve efficacious treatment of bacterial diagnosis and detection. Manganese dioxide (MnO2) nanomaterial has been extensively reported in tumor therapy. Nevertheless, there are few antibacterial reviews of MnO2. Herein, we will discuss the applications of MnO2 in the detection and treatment of bacterial infection, including photodynamic therapy, immunotherapy, improvement of hypoxia, dual-modal combination therapy, reactive oxygen species scavenging, magnetic resonance imaging, optical application of acoustic imaging, and so forth. This review is expected to provide meaningful guidance on further research of MnO2 nanomaterial for antibacterial applications.


Blood conservation and autotransfusion in cardiac surgery.
Blood conservation techniques of withdrawal of blood just before surgery, intraoperative blood salvage with Solcotrans (Solco Basle [UK] Ltd.), and profound hemodilution were used in 14 patients undergoing open heart surgery (group I) and compared with equally matched 14 patients who had profound hemodilution only during cardiopulmonary bypass (CPB) and acted as controls (group II). Group I patients required a mean of 255 mL of homologous blood per patient to achieve a target hemoglobin of 8 g/dL compared to group II patients who required a mean of 1,011 mL per patient (p = 0.0001). By using autologous blood there was a marked reduction in homologous blood exposure. Eight patients in group I and two patients in group II required no homologous blood. No adverse events occurred. In the process of conservation of blood in open heart surgery, we found the combination of the above techniques used in Group I patients to be safe and effective.


Supramolecular Assembly of Multifunctional Collagen Nanocomposite Film via Polyphenol-Coordinated Clay Nanoplatelets.
Functional bionanocomposites have evoked immense research interests in many fields including biomedicine, food packaging, and environmental applications. Supramolecular self-assembled bionanocomposite materials fabricated by biopolymers and two-dimensional (2D) nanomaterials have particularly emerged as a compelling material due to their biodegradable nature, hierarchical structures, and designable multifunctions. However, construction of these materials with tunable properties has been still challenging. Here, we report a self-assembled, flexible, and antioxidative collagen nanocomposite film (CNF) via regulating supramolecular interactions of type I collagen and tannic acid (TA)-functionalized 2D synthetic clay nanoplatelets Laponite (LAP). Specifically, TA-coordinated LAP (LAP-TA) complexes were obtained via chelation and hydrogen bonding between TA and LAP clay nanoplatelets and further used to stabilize the triple-helical confirmation and fibrillar structure of the collagen via hydrogen bonding and electrostatic interactions, forming a hierarchical microstructure. The obtained transparent CNF not only exhibited the reinforced thermal stability, enzymatic resistance, tensile strength, and hydrophobicity but also good water vapor permeability and antioxidation. For example, the tensile strength was improved by over 2000%, and the antioxidant property was improved by 71%. Together with the simple fabrication process, we envision that the resulting CNF provides greater opportunities for versatile bionanocomposites design and fabrication serving as a promising candidate for emerging applications, especially food packaging and smart wearable devices.


Overexpression of microRNA-200c predicts poor outcome in patients with PR-negative breast cancer.
Micro-RNAs are small, noncoding RNAs that act as tumor suppressors or oncogenes. MiR-200c is a member of the miR-200 family; it is known to be dysregulated in invasive breast carcinoma. MiR-200c maintains the epithelial-mesenchymal transition and inhibits cell migration and invasion. Recent studies showed that miR-200c regulated steroid hormone receptors, estrogen receptors (ER), and progesterone receptors (PR). The present study aimed to detect miR-200c in 172 invasive breast carcinoma cases selected from a prospective cohort enrolled in Kuopio, Eastern Finland, between 1990 and 1995. MiR-200c expression was determined with relative q-PCR, and results were compared to clinicopathological variables and patient outcome. We found that PR status combined with miR-200c expression was a significant marker of outcome. High miR-200c expression was associated with reduced survival in PR-negative cases (n = 68); low miR-200c expression indicated reduced survival in PR-positive cases (n = 86) (Cox regression: P = 0.002, OR = 3.433; and P = 0.004, OR = 4.176, respectively). In PR-negative cases, high miR-200c expression was associated with shortened relapse-free survival (Cox regression: P = 0.001, OR = 3.613); increased local/distant recurrence (Logistic regression: P = 0.006, OR = 3.965); and more frequent distant metastasis (Logistic regression: P = 0.015, OR = 3.390). We also found that high grade and low stage tumors were positively correlated with high miR-200c expression (Logistic regression for high grade tumors: P = 0.002, OR = 2.791 and for high stage tumors: P = 0.035, OR = 0.285). Our results indicated that miR-200c may play a role in invasive breast carcinoma. Furthermore, miR-200c combined with PR status provided a refined predictor of outcome. In future, a larger study is required to confirm our results. This data may provide a basis for new research target-progesterone receptor-regulated microRNAs in breast cancer.


Design and synthesis of biotin chain-terminated glycopolymers for surface glycoengineering.
Biotin chain-terminated glycopolymers were generated by cyanoxyl-mediated free-radical polymerization using a biotin-derivatized arylamine initiator with high conversion (75%) and low polydispersity (1.30). Streptavidin-biotinylated glycopolymer binding was verified by SDS-PAGE gel shift assay and patterned glycocalyx-mimetic surfaces successfully fabricated.


Cystic adventitial disease of the popliteal artery: report of two cases.
Cystic adventitial disease (CAD) of the popliteal artery is a rare vascular disorder in which a mucin-containing cyst develops in the adventitial layer of the artery. We report two such cases, each of which was treated differently. The first case was of a 49-year-old man, treated by excision of the involved arterial segment and interposition of an autologous saphenous vein graft. The second case was of a 36-year-old man, treated by local excision of the affected arterial segment and interposition with prosthetic bypass grafting. Both patients presented with rapidly progressing intermittent claudication of the lower extremities, but without remarkable evidence of atherosclerotic disease. Physical examination revealed diminished or absent popliteal, posterior tibial and dorsalis pedis pulses in the lower extremities. Color Doppler ultrasound of the popliteal artery revealed hypoechoic cystic lesions surrounding the vessel, and popliteal arterial stenosis, in both patients. Surgery resulted in immediate improvement of the arterial pulse distal to the lesion. Both patients recovered uneventfully. Thus, resection of the involved artery segment and interposition bypass grafting, using either patient or prosthetic veins, offers favorable results for CAD of the popliteal artery.


Effects produced by infusion of a free radical-generating solution into the diaphragm.
Although studies have examined the susceptibility and pattern of injury induced by infusion of free radical-generating solutions into a number of vital organs, no such investigation has been performed for the diaphragm. The purpose of the present study was to examine the susceptibility of the diaphragm to damage by a free radical-generating solution (iron-ADP complexes). Studies were performed using an in situ canine diaphragmatic strip preparation in which the phrenic artery supplying the strip was cannulated and perfused with blood from the ipsilateral femoral artery. Four groups of studies were performed: (1) a group in which saline was infused into the arterial supply of the diaphragm for 15 min; (2) a group in which a solution of iron-ADP was infused; (3) a group in which both iron-ADP and superoxide dismutase (SOD), a free radical scavenger, were infused; and (4) a group given iron-ADP and denatured SOD. Strip tension and blood flow were monitored during electrically induced diaphragmatic contractions for 15 min before intraphrenic infusions, during the period of infusions, and for 90 min after cessation of infusions. We found that diaphragm tension did not change over time in saline-treated control animals but fell significantly in animals in which iron-ADP was infused. The effects of iron-ADP were largely prevented by concomitant administration of active SOD, but not by denatured SOD. On average, at 90 min after cessation of infusions, tension had fallen to 82 +/- 6, 41 +/- 8, 63 +/- 4, and 28 +/- 9% of its initial value in saline, iron-ADP, iron-ADP/SOD, and iron-ADP/denatured SOD groups, respectively (p < 0.001 for comparison of the four groups, with saline and iron-ADP/SOD groups different from the other two groups). Diaphragm blood flow did not change significantly in any group. These data suggest that free radical-mediated diaphragmatic injury can result in a marked reduction in diaphragm contractility.


Brain responses to success and failure: Direct recordings from human cerebral cortex.
Evaluating the outcome of our own actions is a fundamental process by which we adapt our behavior in our interaction with the external world. fMRI and electrophysiological studies in monkeys have found feedback-specific responses in several brain regions, unveiling facets of a large-scale network predominantly distributed in the frontal lobes. However, a consensus has yet to be reached regarding the exact contribution of each region. The present study benefited from intracerebral EEG recordings in epileptic patients to record directly the neural activity in each of those frontal structures in response to positive and negative feedback. Both types of feedback induced a sequence of high-frequency responses (>40 Hz) in a widespread network involving medial frontal cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and insular cortex. The pre-supplementary motor area (pre-SMA), DLPFC, and lateral OFC showed higher activation in response to negative feedback, while medial OFC and dorsal anterior cingulate cortex (dACC) were more responsive to positive feedback. Responses in the medial prefrontal cortex (pre-SMA and dACC) were sustained (lasting more than 1,000 ms), while responses in the DLPFC, insula, and the OFC were short lasting (less than 800 ms). Taken together, our findings show that evaluating the outcome of our actions triggers gamma-range activity modulations in several frontal and insular regions. Moreover, we found that the timing and amplitude of those gamma-band responses reveal fine-scale dissociations between the neural dynamics of positive versus negative feedback processing.


The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia.
Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, up until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family and recognizes transmembrane proteins (i.e. cargos) having specific sorting signals in their cytosolic domains. Recent studies identified accessory proteins (tepsin, RUSC2 and the FHF complex) that co-operate with AP-4, and cargos (amyloid precursor protein, ATG9A and SERINC3/5) that are exported from the TGN in an AP-4-dependent manner. Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome formation and/or maturation. In addition, mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a form of complicated hereditary spastic paraplegia referred to as 'AP-4-deficiency syndrome' in humans. These findings demonstrated that mammalian AP-4 is required for the development and function of the central nervous system, possibly through its role in the sorting of ATG9A for the maintenance of autophagic homeostasis. In this article, we review the properties and functions of AP-4, and discuss how they might explain the clinical features of AP-4 deficiency.


Comparison of long-term hearing results after vestibular neurectomy, endolymphatic mastoid shunt, and medical therapy.
This study aimed to compare the hearing changes in the long term after vestibular neurectomy, endolymphatic mastoid shunt, and medical treatment in classic Meniere's disease. A retrospective case review was conducted based on audiologic follow-up between 5 and 21 years. The study was performed at two centers in Bari University Hospital, one performing vestibular neurectomy as the first surgical procedure for Meinere's disease and the other, endolymphatic mastoid shunt. Of 68 patients with intractable idiopathic Meniere's disease, 29 underwent middle fossa vestibular neurectomy, and 17 had endolymphatic mastoid shunt; 22 were offered surgery but declined. Outcome measures were puretone average (PTA), speech reception threshold, and speech discrimination score before and after treatment. PTA declined by an average of 9.3 dB in neurectomy patients, 13.3 dB in patients undergoing endolymphatic mastoid shunt, and 18.1 dB in patients who were offered surgery but declined. Patients were subdivided into two cohorts based on their preoperative or initial PTA. In the patients who had PTA scores worse than 50 dB initially, the PTA declined an average of 4.3 dB in the vestibular neurectomy group, 11.5 dB in the endolymphatic sac group, and 4 dB in the nonsurgical group. In the patients with PTA > or = 50 dB initially, the PTA declined an average of of 25.3 dB in the vestibular neurectomy group, 16.1 in the endolymphatic sac group, and 26.2 dB in the nonsurgical group. Although shunt patients with good hearing initially deteriorated less than neurectomy patients and less than patients who declined surgery, the difference was not significant. These results indicate that patients with poor hearing stabilized, while patients with good hearing continued to deteriorate. The same conditions were observed in the patients who had surgery and those who were offered surgery but declined.


An immunopathological study of herpes-associated erythema multiforme.
Any pathogenetic mechanism proposed for erythema multiforme (EM) must account for the prominent mononuclear cell infiltrate in the skin lesions. The purpose of this study was to characterize immunopathologically, with monoclonal antibodies to human leukocyte antigens, the inflammatory cells in early target lesions of recurrent herpes-associated EM. Cryostat sections of snap-frozen skin biopsies were studied by the avidin-biotin immunoperoxidase technique with use of the following monoclonal antibodies: anti-HLA-DR, anti-Leu M5, anti-Leu 4 + 5b, anti-Leu 3a + 3b, anti-Leu 2a, anti-Leu 14, and anti-Leu 6. The dermal mononuclear inflammatory infiltrate in the EM biopsies consisted of monocyte-macrophages and T-lymphocytes, with both helper and suppressor T cells present. Both the dermal inflammatory infiltrate and the overlying keratinocytes were strongly HLA-DR positive. No definite alteration of Langerhans cell number or distribution was noted. These findings are consistent with the characteristics seen in cell-mediated immune reactions in the skin and point to this as a likely immune mechanism for the tissue damage of EM.


IL-17 receptor knockout mice have enhanced myelotoxicity and impaired hemopoietic recovery following gamma irradiation.
IL-17A is a T cell-derived proinflammatory cytokine required for microbial host defense. In vivo expression profoundly stimulates granulopoiesis. At baseline, the hemopoietic system of IL-17R knockout mice (IL-17Ra(-/-)) is, with the exception of increased splenic progenitor numbers, indistinguishable from normal control mice. However, when challenged with gamma irradiation, hemopoietic toxicity is significantly more pronounced in IL-17Ra(-/-) animals, with the gamma irradiation-associated LD(50) being reduced by 150 rad. In spleen-derived T cells, gamma irradiation induces significant murine IL-17A expression in vivo but not in vitro. After sublethal radiation injury (500 rad), the infusion of purified CD4(+) T cells enhances hemopoietic recovery. This recovery is significantly impaired in IL-17Ra(-/-) animals or after in vivo blockade of IL-17Ra in normal mice, resulting in a reduction of hemopoietic precursors by 50% and of neutrophils by 43%. Following sublethal radiation-induced myelosuppression, in vivo overexpression of murine IL-17A in normal mice substantially enhanced granulopoietic restoration in mice with a 4-fold increase in neutrophils and splenic precursors on day 8 (CFU-granulocyte-macrophage/granulocyte-erythrocyte-megakaryocyte-monocyte, CFU-high proliferative potential), as well as 2- and 3-fold increases of bone marrow precursors, respectively. This establishes IL-17A as a hemopoietic response cytokine to radiation injury in mice and an inducible mechanism that is required for recovery of granulopoiesis after radiation injury.


The phlebotomine fauna (Diptera: Psychodidae) of Guaraí, state of Tocantins, with an emphasis on the putative vectors of American cutaneous leishmaniasis in rural settlement and periurban areas.
Phlebotomine sandflies were captured in rural settlement and periurban areas of the municipality of Guaraí in the state of Tocantins (TO), an endemic area of American cutaneous leishmaniasis (ACL). Forty-three phlebotomine species were identified, nine of which have already been recognised as ACL vectors. Eleven species were recorded for the first time in TO. Nyssomyia whitmani was the most abundant species, followed by Evandromyia bourrouli, Nyssomyia antunesi and Psychodopygus complexus. The Shannon-Wiener diversity index and the evenness index were higher in the rural settlement area than in the periurban area. The evaluation of different ecotopes within the rural area showed the highest frequencies of Ev. bourrouli and Ny. antunesi in chicken coops, whereas Ny. whitmani predominated in this ecotope in the periurban area. In the rural settlement area, Ev. bourrouli was the most frequently captured species in automatic light traps and Ps. complexus was the most prevalent in Shannon trap captures. The rural settlement environment exhibited greater phlebotomine biodiversity than the periurban area. Ps. complexus and Psychodopygus ayrozai naturally infected with Leishmania (Viannia) braziliensis were identified. The data identified Ny. whitmani as a potential ACL vector in the periurban area, whereas Ps. complexus was more prevalent in the rural environment associated with settlements.


Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects.
Transient lower esophageal sphincter (LES) relaxations are the major mechanism of gastroesophageal reflux in normal subjects and in most patients with reflux disease. gamma-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter within the central nervous system which is present in regions of the brainstem that are believed to mediate transient LES relaxations. The aim of this study was to investigate the effect of a GABA(B) agonist baclofen on postprandial gastroesophageal reflux and transient LES relaxations. In 20 healthy volunteers, esophageal motility and pH were measured, with the subjects in the sitting position, for 3 hours after a 3000-kJ mixed nutrient meal. On separate days at least 1 week apart, 40 mg oral baclofen or placebo was given 90 minutes before the meal. Baclofen significantly reduced the rate of reflux episodes by more than 60% from 1.0 (0.3-2.7) to 0.3 (0-1.0) per hour (median [interquartile range]). Baclofen also reduced the rate of transient LES relaxations from 5.7 (4.9-7.8) to 2.2 (1.3-3.8) per hour and increased basal LES pressure from 8.7 +/- 1.4 to 10.8 +/- 0.8 mm Hg. In normal human subjects, the GABA(B) agonist baclofen significantly inhibits gastroesophageal reflux by inhibition of transient LES relaxations. These findings suggest that GABA(B) agonists may be useful as therapeutic agents for the management of reflux in patients with gastroesophageal reflux disease.