The microcirculation in two transplantable melanomas of the hamster. I. In vivo observations in transparent chambers.
Twenty-eight transparent chambers were inserted into the cheek pouches of hamsters and daily serial observations made of the changing vasculature of transplants of 2 varieties (A-Mel-4B32, ZGYP1) of amelanotic melanomas. The tumor A-Mel-4B32 grew at a rate which covered 50% of the viewing area in 3--4 days, while the tumor ZGYP1 covered less than 10% of the viewing area at this time and did not cover 50% of the viewing area until 9.5 days after transplantation. The difference in growth rate was not reflected in any differences in the morphology of the vascular network and distribution of the venous arcades.


A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids.
Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. In this study, we found that sanguinarine and chelerythrine induce apoptosis in human CEM T-leukemia cells, and that is accompanied by an early increase in cytosolic cytochrome c that precedes caspases-8, -9 and -3 processing. During apoptosis induction by sanguinarine and chelerythrine, reactive oxygen species (ROS) was rapidly generated and DeltaPsi(mt) dissipated, while Bax, Bcl-2 and Bcl-X((L/S)) proteins' content in the mitochondrial fraction did not change significantly. Caspase-3 activation and DNA fragmentation were considerably inhibited by N-acetyl-cysteine (NAC). Chelidonine induced only a slight release of cytochrome c (12h), parallel to caspase-3 activation. Effect of sanguinarine or chelerythrine towards mitochondria was confirmed by marked changes in morphology of this organelle (3h), while chelidonine did not affect mitochondria intactness. Sanguinarine or chelerythrine also caused an intensive DNA damage in cells in 1h, however a massive increase in number of such impaired cells occurred in 6h, while chelidonine induced intensive DNA damage in 15-20% cells only in 24h. Thus, our results demonstrated that rapid cytochrome c release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8.


Precursors of symbol formation and childhood autism.
The salience of various precursory requirements for the formation of symbols is discussed. The conclusion is drawn that several necessary precursors could be assumed, and two experiments are described that were designed to test for the presence of these precursors in autistic children compared to matched retarded children. First, there was a study of the children's ability to imitate and form internal images, and then there was a study of their development of a concept of object permanence and ability to anticipate. These studies led to the conclusion that the autistic children could form internal images but seemed to lack the ability to manipulate them in a purposeful and meaningful manner, as reflected in their inability to show symbolic imitations and their lack of tendency to use elements of their perceptions that might allow prediction of future events. The findings are discussed in terms of cognitive and social development.


Detection of viable plasmodium ookinetes in the midguts of anopheles coluzzi using PMA-qrtPCR.
Mosquito infection with malaria parasites depends on complex interactions between the mosquito immune response, the parasite developmental program and the midgut microbiota. Simultaneous monitoring of the parasite and bacterial dynamics is important when studying these interactions. PCR based methods of genomic DNA (gDNA) have been widely used, but their inability to discriminate between live and dead cells compromises their application. The alternative method of quantification of mRNA mainly reports on cell activity rather than density. Quantitative real-time (qrt) PCR in combination with Propidium Monoazide (PMA) treatment (PMA-qrtPCR) has been previously used for selectively enumerating viable microbial cells. PMA penetrates damaged cell membranes and intercalates in the DNA inhibiting its PCR amplification. Here, we tested the potential of PMA-qrtPCR to discriminate between and quantify live and dead Plasmodium berghei malarial parasites and commensal bacteria in the midgut of Anopheles coluzzii Coetzee & Wilkerson 2013 (formerly An. gambiae M-form). By combining microscopic observations with reverse transcriptase PCR (RT-PCR) we reveal that, in addition to gDNA, mRNA from dead parasites also persists inside the mosquito midgut, therefore its quantification cannot accurately reflect live-only parasites at the time of monitoring. In contrast, pre-treating the samples with PMA selectively inhibited qrtPCR amplification of parasite gDNA, with about 15 cycles (Ct-value) difference between PMA-treated and control samples. The limit of detection corresponds to 10 Plasmodium ookinetes. Finally, we show that the PMA-qrtPCR method can be used to quantify bacteria that are present in the mosquito midgut. The PMA-qrtPCR is a suitable method for quantification of viable parasites and bacteria in the midgut of Anopheles mosquitoes. The method will be valuable when studying the molecular interactions between the mosquito, the malaria parasite and midgut microbiota.


Estradiol and angiotensin II crosstalk in hydromineral balance: Role of the ERK1/2 and JNK signaling pathways.
The angiotensin II (ANGII) receptor AT1 plays an important role in the control of hydromineral balance, mediating the dipsogenic and natriorexigenic effects and neuroendocrine responses of ANGII. While estradiol (E2) is known to modulate several actions of ANGII in the brain, the molecular and cellular mechanisms of the interaction between E2 and ANGII and its physiological role in the control of body fluids remain unclear. We investigated the influence of E2 (40 μg/kg) pretreatment and extracellular-signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) cell signaling on the dipsogenic and natriorexigenic effects, as well as the neuroendocrine responses to angiotensinergic central stimulation in ovariectomized rats (OVX). We showed that the inhibitory effect of E2 on ANGII-induced water and sodium intake requires the ERK1/2 and JNK signaling pathways. On the other hand, E2 pretreatment prevents the ANGII-induced phosphorylation of ERK and JNK in the lamina terminalis. E2 therapy decreased oxytocin (OT) and vasopressin (AVP) secretion and decreased ERK1/2 phosphorylation in the supraoptic and paraventricular nuclei (SON and PVN, respectively). We found that the AVP secretion induced by ANGII required ERK1/2 signaling, but OT secretion did not involve ERK1/2 signaling. Taken together, these results demonstrate that E2 modulates ANGII-induced water and sodium intake and AVP secretion by affecting the ERK1/2 and JNK pathways in the lamina terminalis and ERK1/2 signaling in the hypothalamic nuclei (PVN and SON) in OVX rats.


Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers.
Diabetic foot ulceration (DFU) is a chronic complication of diabetes that is characterized by impaired wound healing in the lower extremities. DFU remains a major clinical challenge because of poor understanding of its pathogenic mechanisms. Impaired wound healing in diabetes is characterized by decreased angiogenesis, reduced bone marrow-derived endothelial progenitor cell (EPC) recruitment, and decreased fibroblast and keratinocyte proliferation and migration. Recently, increasing evidence has suggested that increased hypoxic conditions and impaired cellular responses to hypoxia are essential pathogenic factors of delayed wound healing in DFU. Hypoxia-inducible factor-1 (HIF-1, a heterodimer of HIF-1α and HIF-1β) is a master regulator of oxygen homeostasis that mediates the adaptive cellular responses to hypoxia by regulating the expression of genes involved in angiogenesis, metabolic changes, proliferation, migration, and cell survival. However, HIF-1 signalling is inhibited in diabetes as a result of hyperglycaemia-induced HIF-1α destabilization and functional repression. Increasing HIF-1α expression and activity using various approaches promotes angiogenesis, EPC recruitment, and granulation, thereby improving wound healing in experimental diabetes. The mechanisms underlying HIF-1α regulation in diabetes and the therapeutic strategies targeting HIF-1 signalling for the treatment of diabetic wounds are discussed in this review. Further investigations of the pathways involved in HIF-1α regulation in diabetes are required to advance our understanding of the mechanisms underlying impaired wound healing in diabetes and to provide a foundation for developing novel therapeutic approaches to treat DFU.


Brachymeria pandora (Crawford) (Hymenoptera: Chalcididae) as a new parasitoid of Thyrinteina leucocerae (Rindge) (Lepidoptera: Geometridae) in Brazil.
This is the first report of Brachymeria pandora (Crawford) (Hymenoptera: Chalcididae)-parasitizing pupae of the eucalyptus defoliator Thyrinteina leucocerae (Rindge) (Lepidoptera: Geometridae) in Brazil.


Effect of certain inhibitors of glycoprotein synthesis on cell fusion induced by vesicular stomatitis virus.
The effect of certain metabolic inhibitors on the fusion of BHK-21 cells induced by vesicular stomatitis virus (VSV) was studied. The polykaryocyte formation in infected cells and virus growth were inhibited by 2-deoxy-D-glucose and D-glucosamine. Host-cell proteins synthesis was suppressed profoundly in both BHK-21-KB and B cells infected with VSV. On the other hand, glycoprotein synthesis was significantly enhanced during the polykaryocyte formation in BHK-21-KB cells, while it was suppressed in BHK-21-B cells which were not sensitive to cell fusion by VSV.


Ergothioneine production by Corynebacterium glutamicum harboring heterologous biosynthesis pathways.
In this study, Corynebacterium glutamicum was engineered to produce ergothioneine, an amino acid derivative with high antioxidant activity. The ergothioneine biosynthesis genes, egtABCDE, from Mycolicibacterium smegmatis were introduced into wild-type and l-cysteine-producing strains of C. glutamicum to evaluate their ergothioneine production. In the l-cysteine-producing strain, ergothioneine production reached approximately 40 mg L-1 after 2 weeks, and the amount was higher than that in the wild-type strain. As C. glutamicum possesses an ortholog of M. smegmatis egtA, which encodes an enzyme responsible for γ-glutamyl-l-cysteine synthesis, the effect of introducing egtBCDE genes on ergothioneine production in the l-cysteine-producing strain was evaluated, revealing that a further increase to more than 70 mg L-1 was achieved. As EgtBs from Methylobacterium bacteria are reported to use l-cysteine as a sulfur donor in ergothioneine biosynthesis, egtB from Methylobacterium was expressed with M. smegmatis egtDE in the l-cysteine-producing strain. As a result, ergothioneine production was further improved to approximately 100 mg L-1. These results indicate that utilization of the l-cysteine-producing strain and introduction of heterologous biosynthesis pathways from M. smegmatis and Methylobacterium bacteria are effective for improved ergothioneine production by C. glutamicum.


Insights into the Structure of Invisible Conformations of Large Methyl Group Labeled Molecular Machines from High Pressure NMR.
Most proteins are highly flexible and can adopt conformations that deviate from the energetically most favorable ground state. Structural information on these lowly populated, alternative conformations is often lacking, despite the functional importance of these states. Here, we study the pathway by which the Dcp1:Dcp2 mRNA decapping complex exchanges between an autoinhibited closed and an open conformation. We make use of methyl Carr-Purcell-Meiboom-Gill (CPMG) NMR relaxation dispersion (RD) experiments that report on the population of the sparsely populated open conformation as well as on the exchange rate between the two conformations. To obtain volumetric information on the open conformation as well as on the transition state structure we made use of RD measurements at elevated pressures. We found that the open Dcp1:Dcp2 conformation has a lower molecular volume than the closed conformation and that the transition state is close in volume to the closed state. In the presence of ATP the volume change upon opening of the complex increases and the volume of the transition state lies in-between the volumes of the closed and open state. These findings show that ATP has an effect on the volume changes that are associated with the opening-closing pathway of the complex. Our results highlight the strength of pressure dependent NMR methods to obtain insights into structural features of protein conformations that are not directly observable. As our work makes use of methyl groups as NMR probes we conclude that the applied methodology is also applicable to high molecular weight complexes.


The identification of age-associated cancer markers by an integrative analysis of dynamic DNA methylation changes.
As one of the most widely studied epigenetic modifications, DNA methylation has an important influence on human traits and cancers. Dynamic variations in DNA methylation have been reported in malignant neoplasm and aging; however, the mechanisms remain poorly understood. By constructing an age-associated and cancer-related weighted network (ACWN) based on the correlation of the methylation level and the protein-protein interaction, we found that DNA methylation changes associated with age were closely related to the occurrence of cancer. Additional analysis of 102 module genes mined from the ACWN revealed discrimination based on two main patterns. One pattern involved methylation levels that increased with aging and were higher in cancer patients compared with normal controls (HH pattern). The other pattern involved methylation levels that decreased with aging and were lower in cancer compared with normal (LL pattern). Upon incorporation with gene expression levels, 25 genes were filtered based on negative regulation by DNA methylation. These genes were regarded as potential cancer risk markers that were influenced by age in the process of carcinogenesis. Our results will facilitate further studies regarding the impact of the epigenetic effects of aging on diseases and will aid in the development of tailored cancer preventive strategies.


Swim bladder function and buoyancy control in pink snapper (Pagrus auratus) and mulloway (Argyrosomus japonicus).
Physoclist fish are able to regulate their buoyancy by secreting gas into their hydrostatic organ, the swim bladder, as they descend through the water column and by resorbing gas from their swim bladder as they ascend. Physoclists are restricted in their vertical movements due to increases in swim bladder gas volume that occur as a result of a reduction in hydrostatic pressure, causing fish to become positively buoyant and risking swim bladder rupture. Buoyancy control, rates of swim bladder gas exchange and restrictions to vertical movements are little understood in marine teleosts. We used custom-built hyperbaric chambers and laboratory experiments to examine these aspects of physiology for two important fishing target species in southern Australia, pink snapper (Pagrus auratus) and mulloway (Argyrosomus japonicus). The swim bladders of pink snapper and mulloway averaged 4.2 and 4.9 % of their total body volumes, respectively. The density of pink snapper was not significantly different to the density of seawater (1.026 g/ml), whereas mulloway were significantly denser than seawater. Pink snapper secreted gas into their swim bladders at a rate of 0.027 ± 0.005 ml/kg/min (mean ± SE), almost 4 times faster than mulloway (0.007 ± 0.001 ml/kg/min). Rates of swim bladder gas resorption were 11 and 6 times faster than the rates of gas secretion for pink snapper and mulloway, respectively. Pink snapper resorbed swim bladder gas at a rate of 0.309 ± 0.069 ml/kg/min, 7 times faster than mulloway (0.044 ± 0.009 ml/kg/min). Rates of gas exchange were not affected by water pressure or water temperature over the ranges examined in either species. Pink snapper were able to acclimate to changes in hydrostatic pressure reasonably quickly when compared to other marine teleosts, taking approximately 27 h to refill their swim bladders from empty. Mulloway were able to acclimate at a much slower rate, taking approximately 99 h to refill their swim bladders. We estimated that the swim bladders of pink snapper and mulloway ruptured after decreases in ~2.5 and 2.75 times the hydrostatic pressure to which the fish were acclimated, respectively. Differences in buoyancy, gas exchange rates, limitations to vertical movements and acclimation times between the two species are discussed in terms of their differing behaviour and ecology.


Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and impact on health care charges.
Asthma is a common and costly condition. Concomitant asthma and allergic rhinitis (AR) have been shown to increase the medication costs for people with asthma. No studies have compared medical care costs of those with and without concomitant AR. We sought to determine the prevalence and incremental medical care costs of concomitant AR. For each member of a population-based asthma cohort, we used all their medical charts within Olmsted County to record age at first diagnosis of asthma; the presence and age of any diagnosis of AR; and the total, ambulatory, and respiratory care-related costs of medical care. Costs were compared for age- and sex-specific strata of people with asthma who did and did not have AR. AR was most commonly diagnosed in people whose asthma was diagnosed before age 25 (prevalence of 59%) and uncommonly diagnosed in anyone after age 40 (prevalence <15%). Yearly medical care charges were on average 46% higher for those with asthma and concomitant AR than for persons with asthma alone, controlling for age and sex. We were unable to assess the impact of treatment of AR on medical care charges. Physicians should consider the diagnosis of AR (prevalence >50%) in all symptomatic children and young adults with asthma. Further evaluation is necessary to evaluate the ability of treatment to decrease the incremental costs of AR in persons with asthma.


Pancreatic Cancer and Diabetes Mellitus.
The relationship between pancreatic ductal adenocarcinoma (PDAC) and diabetes mellitus (DM) is complex. We reviewed the recent medical literature regarding the effect of anti-diabetic medication on PDAC risk and survival, risk of PDAC in DM, and role of DM in early detection of PDAC. Studies report that while some anti-diabetic medications (e.g., metformin) may decrease the risk of PDAC, others (insulin, sulfonylureas and incretin-based therapies) may increase the risk. However, these observations may be subject to protopathic biases. Metformin's anti-tumor activity may have influence overall survival of PDAC, but epidemiological reports have largely been inconsistent to defend these findings due to heterogeneous methodologies. There is congruent data to support the association between DM and PDAC, with an inverse relationship to DM duration. Older subjects with new-onset DM are the only known high-risk group for PDAC, and strategy using this group for early detection has led to development of clinical risk prediction models that define a very high-risk PDAC group. Role of anti-diabetic medication in PDAC risk modification or survival is controversial. With successful efforts to distinguish type 2-DM from PDAC-DM using risk-stratifying models, there is an opportunity to initiate screening protocols for early detection of PDAC in a sub-set of DM subjects.


Short-term changes in sleep, mastery & stress: impacts on depression and health in dementia caregivers.
Dementia caregiving is stressful and can result in negative health outcomes. Understanding the intermediate dynamic changes in caregiving may help nurses target interventions. The purposes of this study were to measure short-term changes in sleep, mastery, and stress in dementia caregivers and to explore their impacts on caregiver depression and health. Seventy-four caregivers were measured at baseline, 4, and 8 weeks for changes in global mastery, caregiver mastery, sleep quality, perceived stress, depression, and health. Over the 8 weeks, changes were observed in sleep, mastery, stress, and health measures, indicating support for the dynamic and complex nature of dementia caregiving. Sleep and perceived stress made unique contributions to depression, but the contributions to health varied. Clinical implications for nurses are to assess caregivers frequently and reinforce successful interventions periodically as caregiving evolves.


Structural insights into impact of Y134F mutation and discovery of novel fungicidal compounds against CYP51 in Puccinia triticina.
Sterol 14α-Demethylase Cytochrome P450 (CYP51) protein involved in ergosterol biosynthesis pathways turn out to be a crucial target for the fungicidal compound. However, the recognition mechanism and dynamic behavior of CYP51 in wheat leaf rust pathogen, Puccinia triticina, is still obscure. Previously, a mutation at position 134 (Y134F) was reported in five European isolates of P. triticina, conversely, structural basis of this mutation remains unclear. To address this problem, three-dimensional structure of CYP51 protein from P. triticina was successfully built using homology modeling approach. To assess the protein structure stability, wild and mutant-type CYP51 proteins bound with azole fungicide was subjected to 50 ns molecular dynamics (MD) simulations run. Observably, the comparative protein-ligand interaction analysis and binding free energy results revealed that impact of the mutation on the thermodynamics and conformational stability of the CYP51 protein was negligible. In addition, we carried out structure-based virtual screening and identified potent novel fungicidal compounds from four different databases and libraries. Consequently, through MD simulation and thermodynamic integration, four novel compounds such as CoCoCo54211 (CoCoCo database), ZINC04089470 (ZINC database), Allyl pyrocatechol 3,4 diacetate (Natural compound library), and 9-octadecenoic acid (Traditional Chinese Medicine database) has been predicted as potent fungicidal compound against CYP51 with XPGlide docking score of -11.41, -13.64, -7.40, and -6.55 kcal/mol, respectively. These compounds were found to form hydrogen bonds with heme group of CYP51, subsequently disturbing the stability and survival of fungus and can be used to control leaf rust in wheat.


Techniques for Open Surgical Resection of Brain Metastases.
Brain metastases are the most common intracranial tumor and a leading cause of morbidity and mortality for patients with systemic cancer. En bloc surgical resection of brain metastases improves survival, local recurrence rates, and functional independence in patients with up to three metastases and controlled extracranial disease. Modern techniques and technologies provide the neurosurgeon with minimally invasive approaches, such as keyhole craniotomies and tubular retractors. Preoperative planning for tumors located in eloquent regions includes mapping with functional MRI and diffusion tensor imaging, and intraoperative mapping and monitoring with electrophysiologic techniques under general or awake anesthesia to preserve normal neurologic function.


Course of insight, depression and suicidality in inpatients with first-episode schizophrenia who received group psychoeducation.
We aimed to investigate whether gaining insight through psychoeducation for first-episode schizophrenia is associated with increased suicidality. We conducted a secondary analysis of a prospective cohort study that included inpatients with first-episode schizophrenia who attended a group psychoeducation program during their admission. The group psychoeducation program consisted of four weekly sessions provided by a multidisciplinary team. The primary outcome was the correlation between changes in insight and suicidality. We also examined whether change in insight was associated with changes in hopelessness and depression. We measured insight using the Birchwood Insight Scale. Suicidality, hopelessness and depression were measured using the Calgary Depression Rating Scale for Schizophrenia. A total of 125 people participated in the educational program. The Spearman's correlation coefficient between changes in insight and suicidality was -0.14 (95% confidence interval, -0.31 to 0.04; p = .12). Similarly, gain in insight did not significantly correlate with change in depression (0.01, 95% confidence interval, -0.17 to 0.18; p = .93) and change in hopelessness (0.01, 95% confidence interval, -0.16 to 0.19; p = .88). We observed almost no association between gaining insight and suicidality after a group psychoeducation program in inpatients with first-episode schizophrenia.


Wild and cultivated barleys show similar affinities for mineral nitrogen.
The kinetics of net ammonium influx were very similar among several cultivars of barley (Hordeum vulgare) and several accessions of the wild taxa H.v. spontaneum and H. jubatum. For net nitrate influx, variation was greater among accessions than among species; accessions from warmer climates had faster rates than those from colder climates. These data indicate that domestication of barley has not reduced its affinity for mineral nitrogen.


Milling byproducts are an economically viable substrate for butanol production using clostridial ABE fermentation.
Butanol is a platform chemical that is utilized in a wide range of industrial products and is considered a suitable replacement or additive to liquid fuels. So far, it is mainly produced through petrochemical routes. Alternative production routes, for example through biorefinery, are under investigation but are currently not at a market competitive level. Possible alternatives, such as acetone-butanol-ethanol (ABE) fermentation by solventogenic clostridia are not market-ready to this day either, because of their low butanol titer and the high costs of feedstocks. Here, we analyzed wheat middlings and wheat red dog, two wheat milling byproducts available in large quantities, as substrates for clostridial ABE fermentation. We could identify ten strains that exhibited good butanol yields on wheat red dog. Two of the best ABE producing strains, Clostridium beijerinckii NCIMB 8052 and Clostridium diolis DSM 15410, were used to optimize a laboratory-scale fermentation process. In addition, enzymatic pretreatment of both milling byproducts significantly enhanced ABE production rates of the strains C. beijerinckii NCIMB 8052 and C. diolis DSM 15410. Finally, a profitability analysis was performed for small- to mid-scale ABE fermentation plants that utilize enzymatically pretreated wheat red dog as substrate. The estimations show that such a plant could be commercially successful.Key points• Wheat milling byproducts are suitable substrates for clostridial ABE fermentation.• Enzymatic pretreatment of wheat red dog and middlings increases ABE yield.• ABE fermentation plants using wheat red dog as substrate are economically viable. Graphical abstract.


A follow-up survey of patients with acquired angioedema due to C1-inhibitor deficiency.
Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare form of bradykinin-mediated angioedema. It is diagnosed by complement testing; its treatment consists of the management of angioedema (AE) attacks and of underlying disease. Evaluate the results of the clinical follow-up of patients with C1-INH-AAE. Between 1999 and 2020, 3938 patients with angioedema were evaluated, and 17 diagnosed with acquired C1-INH deficiency were followed-up. Mean age of the 17 patients was 61 years at diagnosis. In 33%, ACE inhibitors provoked AE attacks. Autoantibodies against C1-INH were detected in 10 patients at diagnosis and in a further patient during follow-up. The AE attacks involved the skin in 70.6%, the upper airways in 41.2% and the tongue/lip in 52.9% of patients. Twelve of the 17 patients had an underlying condition, mainly (n = 11) lymphoproliferative disease. In 10 patients diagnosed with a haematological disorder, AAE symptoms preceded the onset of the latter. One patient has not experienced an AE attack since diagnosis. Twelve patients were treated for angioedema attacks, and 32% of the attacks required acute treatment. PdC1-INH was used to relieve AE attacks, and rituximab for the treatment of underlying disease (in six patients). Six patients had multiple AE attacks before any treatment. The symptom-free period increased in five patients after the on-demand administration of pdC1-INH concentrate and following treatment of the underlying disease in two patients. Early diagnosis of C1-INH-AAE and underlying disease is indispensable to reduce disease burden by introducing appropriate, individualized treatment and regular follow-up.


Properties and serum levels of pregnancy-associated variant of human transcortin.
The amino acid composition, N- and C-terminal amino acid sequences, and the basic physicochemical and immunochemical properties of the recently discovered pregnancy-associated molecular variant of human transcortin (Strel'chyonok, O.A., Avvakumov, G.V. and Akhrem, A.A. (1984) Carbohydr. Res. 134, 133-140) have been found to be identical to those of transcortin from normal donor serum. This suggests the identity of polypeptide moieties of the two glycoproteins. The transcortin variant has a lower isoelectric point (3.5-4.1) than normal transcortin (3.6-4.2), and different electrophoretic mobility in low-porosity polyacrylamide gel (one band versus two for normal transcortin). These differences can be reasonably explained by different organization of the carbohydrate moieties of these glycoproteins due to diverse post-translational modification of a single polypeptide chain. The levels of transcortin variant in the maternal venous serum throughout normal gestation (447 donors in all) and on the fifth day after delivery, as well as in umbilical cord serum and extracts of term placenta, have been measured by a radioimmune assay. Analysis of the data obtained allowed us to conclude that the biosynthesis of pregnancy-associated transcortin variant occurs in some organ of the maternal organism rather than in the feto-placental system, and it is a characteristic of pregnancy as a unique physiological state of the female organism rather than a phenomenon caused by individual features of certain women. We assume that the transcortin variant takes part in the guided transport of corticosteroids and/or progestins into some tissues that develop in the course of gestation.


Technical solution for an interactive functional MR imaging examination: application to a physiologic interview and the study of cerebral physiology.
Studies with functional magnetic resonance (MR) imaging produce large unprocessed raw data sets in minutes. The analysis usually requires transferring of the data to an off-line workstation, and this process frequently occurs after the subject has left the MR unit. The authors describe a hardware configuration and processing software that captures whole-brain raw data files as they are being produced from the MR unit. It then performs the reconstruction, registration, and statistical analysis, and displays the results in seconds after completion of the MR image acquisition.


A prospective phase II study of magnetic resonance imaging guided hematopoietical bone marrow-sparing intensity-modulated radiotherapy with concurrent chemotherapy for rectal cancer.
To reduce acute hematologic toxicity (HT) in rectal cancer patients treated with neoadjuvant concurrent chemoradiotherapy by sparing the hematopoietical bone marrow (BM) indentified by magnetic resonance (MR). A total of 35 staged II/III rectal cancer patients were prospectively enrolled. MR images of pelvis were fused with the simulating CT images. Active BM indentified by MR was contoured as an organ at risk in the treatment plan. The neoadjuvant treatment regimen consisted of 50 Gy of radiation delivered in 25 fractions, 5 days per week, with concurrent daily capecitabine (1650 mg/m(2)/day, twice daily during RT course) and weekly oxiliplatin 50 mg/m(2)/qw. Multivariable linear regression model is used to test correlation between HT and dose-volume of BM. Thirty-one patients (88.6%) had stage T3-4 disease, and 30 patients (85.7%) had node-positive disease. The median age of cohort was 55 years (range 28-73 years). Only 9 (25.7%), 6 (17.1%), 1 (2.9%) and 1 (2.9%) experienced acute Grade 2-4 leukopenia, neutropenia, anemia and thrombocytopenia, respectively. Multivariable linear regression revealed increased BM-V5 was significantly associated with decreased WBC nadirs (p = 0.005), decreased ANC nadirs (p = 0.002), and decreased PLT nadirs (p = 0.017). No dose-volume parameters of BM were found to be related with decreased Hb. The irradiated volume of pelvic BM identified by MR is associated with HT in rectal cancer patients undergoing neoadjuvant concurrent chemoradiotherapy.


Serum biomarkers of cerebral cellular stress after self-limiting tonic clonic seizures: An exploratory study.
It has been debated for decades whether single, self-limited seizures damage cerebral cells. Meanwhile, very sensitive measurements of biomarkers have become available, i.e. tau, neurofilament protein light (NFL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminate hydrolase L1 (UCHL-1), which we explored in this study. Adult patients of the epilepsy monitoring unit were admitted to the study after written consent. Blood samples were drawn at baseline, immediately after a TCS and after two, six and 24 h. The markers were measured from frozen samples with a single-molecule array (SIMOA). 20 patients and 20 seizures were included. All markers showed subtle but significant postictal increases and returned to normal within the next few hours (p < 0.05). An increase of at least 100 % from baseline was noted in 30 % of patients for tau, 25 % for UCHL-1 and 15 % for GFAP, while NFL levels never increased above 100 %. Lactate was slightly correlated with the tau increase (r = 0.47, p = 0.037), leukocytes were correlated with postictal changes of GFAP (r = 0.68 p = 0.001). Our data supports the assumption that significant cerebral stress occurs in some but not all self-limited TCS. The postictal inflammatory response in particular seems to play an important role.


Tensile bond strength of dental adhesives to dentin and enamel.
This study compared the tensile bond strengths of an unfilled resin bonding agent and four proprietary dentin bonding agents to dentin and acid-etched enamel. Forty-eight hours after bonding, 10 dentin-bonded teeth and 10 enamel-bonded teeth for each material were loaded in tension in an Instron Universal Testing Machine until bond failure. The remaining specimens were stored in a water bath for six months and then tested in a similar manner. At the end of six months, Universal Bond and Tenure (3-step) had bond strengths significantly greater than those of the other agents. All bonding agents, except Tenure (3-step), showed a significant decrease in tensile bond strength to both dentin and enamel after six months (p less than 0.0001).


Tolerable and curable treatment in HIV/HCV co-infected patients using anti-HCV direct antiviral agents: a real-world observation in China.
No brand direct-acting antiviral agents (DAAs) are available for treatment of HIV-1/HCV co-infected patients in China. This study aimed to observe the therapeutic efficacy and safety of generic DAAs for affected Chinese patients. Real-world setting to elucidate whether DAAs were tolerated and effective in HIV-1/HCV co-infected patients. 176 HIV-1/HCV co-infected patients received anti-HCV DAA treatment together with ART regimens for HIV infection. Among the 176 patients, 99 patients were treated with SOF + DCV ± RBV, 60 patients were treated with SOF + LDV ± RBV, and 17 patients received SOF + RBV ± Peg-IFN regimens, for 12 or 24 weeks, respectively. The primary endpoint was undetectable HCV RNA 12 weeks after therapy was completed (SVR12). Data pertaining to safety and adverse events were analyzed. 151/176 HIV-1/HCV co-infected patients finished the treatment and 12-week follow-up. SVR12 for the patients treated with regimens of SOF + DCV, SOF + DCV+RBV, SOF + Peg-IFN+RBV, SOF + RBV, SOF + LDV, and SOF + LDV+RBV for 12 or 24 weeks was 100% (75/75), 100% (11/11), 100% (14/14), 100% (2/2), 95.2% (40/42), and 100% (7/7), respectively. HIV-1/HCV co-infected patients with liver cirrhosis achieved well SRV12. Notably, there was no significant difference in adverse effects among patients with different baseline CD4+ T-cell count in those who received DAA regimens with or without Peg-IFN and RBV. We showed generic SOF + DCV and SOF + LDV regimens were well tolerated and with high efficiency. Patient's baseline CD4+ T-cell count did not exhibit significant difference in adverse effects.


Author Correction: Collaborative networks in gene editing.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Granulocyte-macrophage colony-stimulating factor as a mediator of autoimmunity in multiple sclerosis.
Autoreactive, myelin-specific, CD4+ T cells have a central role in multiple sclerosis (MS) pathogenesis; however the exact phenotype characteristics of these cells remain elusive. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression has emerged as the main pathological signature of the encephalogenicity in both T and B cell compartment. In this review we have summarized the current data supporting GM-CSF relevance in MS pathophysiology, in the context of both immunomodulatory and neuroinflammatory processes; as well as the potential cellular sources of this stimulating factor, including different T and B cell subsets.


Ultrasonographically-guided fine-needle aspiration cytology in the diagnosis of colonic lesions.
The use of fine-needle aspiration cytology (FNAC) in the diagnosis of colonic lesions was investigated. Some 22 patients (median age 71 years) with a colonic lesion identified on abdominal ultrasonography underwent ultrasonographically-guided FNAC using a 21-G needle. The sample was checked immediately by a cytopathologist for adequacy. Eighteen patients had colonic carcinoma; aspiration cytology detected malignant epithelial cells consistent with colonic carcinoma in 17 patients and severely dysplastic cells in one patient. The sensitivity and specificity of ultrasonographically-guided FNAC in the diagnosis of colonic carcinoma was 94 and 100 per cent respectively. The remaining four patients had a diagnosis of ileocaecal tuberculosis, ileocaecal Crohn's disease, and metastatic adenocarcinoma in the liver with no identifiable primary (two patients). One demonstrated granulomata, grew acid-fast bacilli and the patient was treated for tuberculosis. One had inflammatory cells and the patient was found to have Crohn's disease on histology. The remaining two patients had confirmed metastatic adenocarcinoma in the liver on aspiration cytology but suspected colonic lesions were found to be benign on cytological examination and no primary lesion was subsequently demonstrated. There were no complications of FNAC and patients complained of minimal discomfort. There has been no evidence of tumour recurrence with a median follow-up of 12 (range 1-25) months. Ultrasonographically-guided FNAC is a valid method for the diagnosis of colonic tumours.


Expression profile of total VEGF, VEGF splice variants and VEGF receptors in the myocardium and arterial vasculature of diabetic and non-diabetic patients with coronary artery disease.
Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and is implicated in the development of diabetic microvascular and macrovascular disease. The expression of total VEGF, VEGF splice variants (VEGF(121), VEGF(145), VEGF(148), VEGF(165), VEGF(183) and VEGF(189)), VEGFR-1 and VEGFR-2, was investigated in biopsies from the right atrium and left internal mammary artery (LIMA) of 32 non-diabetic and 20 diabetic patients undergoing coronary artery bypass grafting. Diabetes was independently negatively correlated to total VEGF mRNA expression in atrium. Total VEGF, VEGF(121) and VEGF(165) mRNA levels were upregulated in the LIMA of diabetics vs. non-diabetics. The expression of VEGF receptors in atrium and LIMA was similar between these groups. VEGF(121) and VEGF(165) were the major variants expressed, followed by VEGF(189) and VEGF(183), while VEGF(148) and VEGF(145) were detected in small amounts. The expression profile of VEGF splice variants displayed significant heterogeneity between the examined tissues. This is the first study to quantify VEGF splice variants expression in cardiac and vascular tissue. Our results could help elucidate the role of VEGF splice variants in diabetic complications.


Resistance and uptake of cadmium by yeast, Pichia hampshirensis 4Aer, isolated from industrial effluent and its potential use in decontamination of wastewater.
Pichia hampshirensis 4Aer is first ever used yeast for the bioremediation of environmental cadmium (Cd(+2)) which could maximally remove 22 mM/g and 28 mM/g Cd(+2) from aqueous medium at lab and large scales, respectively. The biosorption was found to be the function of temperature, pH of solution, initial Cd(+2) concentration and biomass dosage. Competitive biosorption was investigated in binary and multi-metal system which indicated the decrease in Cd(+2) biosorption with increasing the competitive metal ions attributed to their higher electronegativity and larger radius. FTIR analysis revealed the active participation of amide and carbonyl moieties in Cd(+2) adsorption confirmed by EDX analysis. Electron micrographs summoned further surface adsorption and increased cell size due to intracellular Cd(+2) accumulation. Cd(+2) was the causative agent of some metal binding proteins as well as prodigious increase in glutathione and other non-protein thiols levels which is the crucial for the yeast to thrive oxidative stress generated by Cd(+2). Our experimental data were consistent with Langmuir as well as Freundlich isotherm models. The yeast obeyed pseudo second order kinetic model which makes it an effective biosorbent for Cd(+2). High bioremediation potential and spontaneity and feasibility of the process make P. hampshirensis 4Aer an impending foundation for green chemistry to exterminate environmental Cd(+2).


Indomethacin retinopathy: case report and review.
The case of a 33-year-old man with probable indomethacin retinopathy is presented. The relevant literature is reviewed and the differences between our case and those previously reported are noted. Our patient appears to have suffered severe and irreversible ocular damage due to the very high dose of indomethacin ingested over a prolonged period.


Defining the genetic architecture of human developmental language impairment.
Language is a uniquely human trait, which poses limitations on animal models for discovering biological substrates and pathways. Despite this challenge, rapidly developing biotechnology in the field of genomics has made human genetics studies a viable alternative route for defining the molecular neuroscience of human language. This is accomplished by studying families that transmit both normal and disordered language across generations. The language disorder reviewed here is specific language impairment (SLI), a developmental deficiency in language acquisition despite adequate opportunity, normal intelligence, and without any apparent neurological etiology. Here, we describe disease gene discovery paradigms as applied to SLI families and review the progress this field has made. After review the evidence that genetic factors influence SLI, we discuss methods and findings from scans of the human chromosomes, including the main replicated regions on chromosomes 13, 16 and 19 and two identified genes, ATP2C2 and CMIP that appear to account for the language variation on chromosome 16. Additional work has been done on candidate genes, i.e., genes chosen a priori and not through a genome scanning studies, including several studies of CNTNAP2 and some recent work implicating BDNF as a gene x gene interaction partner of genetic variation on chromosome 13 that influences language. These recent developments may allow for better use of post-mortem human brain samples functional studies and animal models for circumscribed language subcomponents. In the future, the identification of genetic variation associated with language phenotypes will provide the molecular pathways to understanding human language.


Endothelial and smooth muscle cells dysfunction distal to recanalized chronic total coronary occlusions and the relationship with the collateral connection grade.
This study sought to assess the vascular function in patients with chronic total coronary occlusions (CTO) immediately after successful percutaneous recanalization and its relation with the pre-existing collateral circulation. CTOs represent a long-acting occlusion of a coronary vessel, in which the progressively developed collateral circulation may limit ischemia and symptoms. However, it is unknown if the coronary segment distal to the occlusion has a preserved vascular function. We prospectively enrolled 19 consecutive patients, after percutaneous coronary intervention of a CTO. Luminal diameter, measured by quantitative coronary angiography, and coronary blood flow at level of epicardial coronary artery distal to the treated CTO was assessed before and after administration of acetylcholine (Ach), adenosine, and nitroglycerin (NTG). Collaterals were assessed angiographically by grading of Rentrop and of collateral connections (CC1: threadlike continuous connection; CC2: side branch-like connection). Overall, Ach and adenosine caused coronary artery vasoconstriction (p=0.001 and p=0.004, respectively), whereas NTG failed to induce vasodilation (p=0.084). Coronary blood flow significantly decreased with Ach (p=0.005), significantly increased with NTG (p=0.035), and did not change with adenosine (p=0.470). Patients with CC2 collaterals (n=8) had less vasoconstriction response and reduction in coronary blood flow after Ach (p=0.005 and p=0.008, respectively), and better vasomotor response to NTG (p=0.029) than patients with CC1 collaterals (n=11). Significant endothelial and smooth muscle dysfunction is present in the distal segments of successfully recanalized CTOs, and that seems to be more pronounced in the presence of a low grading of collateral circulation.


Percutaneous transhepatic angioplasty and stent implantation for prehepatic portal vein obstruction.
Twenty-nine months after a Whipple procedure for pancreatic carcinoma, a 47-year-old woman developed esophageal variceal bleeding. Percutaneous transhepatic portography revealed a severe stenosis of the portal vein with prehepatic portal hypertension and collateral circulation mainly to the gastric and esophageal veins. Percutaneous transhepatic balloon angioplasty was used to dilate the stenoses, but it did not remove the stenosis sufficiently. Therefore, an 8-mm, self-expandable stent was implanted, creating a nearly normal lumen without a pressure gradient. Portal hypertension was relieved, and the patient had no recurrent variceal bleeding for the 5 months up to her death.


Systems integration.
The paper presents a view of systems integration, from an ergonomics/human factors perspective, emphasising the process of systems integration as is carried out by humans. The first section discusses some of the fundamental issues in systems integration, such as the significance of systems boundaries, systems lifecycle and systems entropy, issues arising from complexity, the implications of systems immortality, and so on. The next section outlines various generic processes for executing systems integration, to act as guides for practitioners. These address both the design of the system to be integrated and the preparation of the wider system in which the integration will occur. Then the next section outlines some of the human-specific issues that would need to be addressed in such processes; for example, indeterminacy and incompleteness, the prediction of human reliability, workload issues, extended situation awareness, and knowledge lifecycle management. For all of these, suggestions and further readings are proposed. Finally, the conclusions section reiterates in condensed form the major issues arising from the above.


Application of tetraoxadiaza-crown ether derivatives as chiral selector modifiers in capillary electrophoresis.
Two new diaza-crown ether derivatives (R-1, RS-1) have been synthesized from 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane and tested as potential chiral selectors in capillary electrophoresis (CE) for the chiral separation of five amino acid derivatives. The individual use of the selectors did not lead to chiral differentiation. However, they enhanced the enantioselective effect of different cyclodextrins in dual selector systems. In this paper, we report the effect of different substituted diaza-crown ether derivatives on the separation results obtained in dual systems with cyclodextrins.


Suprapubic micturating cystourethrography in infants.
Contrast medium may be safely and easily placed in the bladder by suprapubic puncture. Samples of clean urine may be obtained at the same examination. The technique and its advantages are described in detail.


Evaluation of choroidal thickness in psoriasis using optical coherence tomography.
The purpose of this study was to evaluate choroidal thickness (CT) in patients with psoriasis using enhanced depth imaging optical coherence tomography (EDI-OCT) and to determine its relationship with psoriasis activity indices. In this prospective study, EDI-OCT images were obtained in consecutive patients with psoriasis and in age-gender-matched healthy individuals. Comprehensive ophthalmic examination and EDI-OCT evaluation were performed. CT was measured in the subfoveal area. Correlation analyses were performed to identify the relationship of the CT with disease duration and clinical disease activity score. In total, 65 individuals were evaluated in this study, 35 with psoriasis and 30 controls. The mean disease duration of the patients with psoriasis was 15.7 ± 8.8 years (0.3-34 years). There was no difference between groups with respect to age and gender (p = 0.695 and p = 0.628, respectively). Five of the 35 patients with psoriasis had anterior uveitis. None of the patients with psoriasis had signs of posterior uveitis. CT was significantly higher in the psoriasis group than that of control subjects (p < 0.001). The mean central foveal thickness was comparable between groups (p = 0.672). There was also no significant correlation between EDI-OCT, disease activity score, and disease duration (p < 0.05). Choroidal thickness is increased in psoriasis patients. Large serial and comparative studies are necessary to evaluate EDI-OCT, an examination that may be helpful in understanding the effects of psoriasis on the eye and its pathophysiology.


Research on Cognitive Function in Anxious Depression Patients in China.
This study aimed to evaluate cognitive function in patients with anxious depression. This was a part of the "Objective Diagnostic Indicators and Individualized Drug Intervention of Major Depressive Disorder (MDD)" study. All participants, including patients with MDD and healthy controls (HCs), completed the 17-item Hamilton Depression Scale (HAMD17) and the Hamilton Anxiety Scale (HAMA). Anxious depression was defined as a HAMD17 anxiety/somatization factor score ≥7. Cognitive function was assessed at baseline and at the end of week 8. HC cognitive function was assessed at baseline. A total of 1048 people were included in the analysis, including 328 patients in the anxious depression group (G1=328), 221 patients in the MDD without anxious depression group (G2=221), and 499 in the HC group (G3=499). There were significant differences in the HAMA at baseline (t=13.050, p<0.001), HAMD17 at baseline (t=16.722, p<0.001), and HAMA at weekend 8 (z=-3.477, p=0.001) between G1 and G2. Cognitive functioning on the Hopkins Verbal Learning Test-Revised (HVLT-R) (t=2.948, p=0.003) and the Brief Visual Memory Test-Revised (BVMT-R) (t=2.843, p=0.005) was better in G1 than in G2 at baseline. Cognitive functioning on the HVLT-R (OR=1.081, p=0.006) was better in G1 than in G2 at weekend 8. The Stroop-color-word test (SCWT) (OR=0.976, p=0.004) and the Continuous Performance Test (CPT) (OR=0.698, p=0.007) showed significant differences at baseline; however, after the acute treatment phase, there were no significant differences in executive function (assessed by SCWT) (p=0.148) or attention/vigilance (assessed by CPT) (p=0.416) between G1 and G3. Patients with anxious depression have more severe depressive symptoms but better cognitive function, especially for verbal learning, compared with nonanxious depression patients. After the acute treatment phase, executive function and attention/vigilance in anxious depression patients may be remitted.


Eigenvalue effective population numbers for populations that vary cyclically in size.
Four types of effective population numbers have been discussed in the literature on population genetics. It was shown by Wang and Pollak [Math. Biosci. 166 (2000) 1] that if a large random mating dioecious population varies cyclically in size and the population is followed over a whole cycle, the variance, inbreeding and mutation effective numbers are equal. It was also shown, in a special case, that the variance effective number, N(eV), is equal to the eigenvalue effective number, N(eE). The former is related to the long-term rate at which the variance between lines increases and the latter is computed from the largest non-unit eigenvalue of the matrix of transition probabilities governing the change with time of frequencies of an allele among males and females. It is shown in this paper that N(eE) is quite generally at least approximately the same as N(eV) if the numbers of males and females are always large. Both autosomal and sex-linked loci are considered and the theory allows for reproduction partially by a regular system of inbreeding.


Genetic identification of rat liver carboxylesterases isolated in different laboratories.
Six carboxylesterases previously isolated from rat liver microsomes, characterized in Brussels and in Kiel, were compared with genetically defined liver esterases of various reference strains using polyacrylamide gel electrophoresis and isoelectric focusing. The six liver carboxylesterases were identified as alloenzymic forms of ES-3, ES-4, ES-8/ES-10 and ES-15 according to the genetic nomenclature recommended by van Zutphen (Van Zutphen, L.F.M. (1983) Transplant. Proceed. 15, 1687-1688). The genetic and biochemical characteristics of the four isoenzymes are summarized, and their identity with several other drug-metabolizing esterases/amidases and lipases of rat liver endoplasmic reticulum is discussed.


Incidence of hypertension after marrow transplantation among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis.
We investigated the frequency of hypertension (sustained diastolic blood pressure greater than or equal to 90 mmHg) in 112 patients given HLA-identical marrow grafts. Patients were conditioned with 2 X 60 mg/kg of cyclophosphamide and 6 X 2 Gy of total body irradiation and randomized to receive as graft-versus-host disease prophylaxis either the standard methotrexate regimen (n = 61) or cyclosporine (n = 51), starting on day -1 as 12.5 mg/kg/d orally or as 3 mg/kg/d i.v. and later converting to p.o. when oral intake was tolerated. Kaplan-Meier estimates indicate a 60% incidence of hypertension in the first 120 d in patients given cyclosporine (median time to onset: 4 d post transplant) compared to 20% in patients given methotrexate (P less than 0.0001). Multifactorial analysis using a Cox regression model showed that cyclosporine was was the most significant risk factor for developing hypertension (relative risk: 32.1, P less than 0.0001). In addition, glucocorticoids, used for treatment of GVHD, were associated with an increased risk for hypertension (relative risk 7.2, P less than 0.0001). Age, sex, underlying disease, cyclosporine trough levels, and renal function had no significant association with hypertension. Early therapy of hypertension in cyclosporine-treated patients appears to be indicated.


Predictors for recurrent primary intracerebral hemorrhage: a retrospective population-based study.
Underlying comorbidities, previous strokes, and medication may increase the risk for primary intracerebral hemorrhage (PICH) and its recurrence. The aim of this study was to determine the independent predictors for recurrent PICH. We identified 961 subjects with first-ever PICH from 1993 to 2008 among the population of Northern Ostrobothnia, Finland. Hospital and death records were reviewed and data on drug use were obtained from the national register of prescribed medicines. Kaplan-Meier survival curves and Cox proportional hazards models were used to demonstrate predictors for recurrence of PICH. Total follow-up time of the 961 patients was 3481 person-years. During the follow-up time, 58 subjects had altogether 68 recurrent PICHs. The annual average incidence of first recurrence was 1.67%. Cumulative 5- and 10-year incidence rates were 9.6% and 14.2%, respectively. In univariable analysis, history of ischemic stroke, diabetes mellitus, and aspirin use were associated with a higher recurrence rate. In multivariable analysis, only previous ischemic stroke (adjusted hazard ratio, 2.22; 95% confidence interval, 1.22-4.05; P=0.009) independently predicted PICH recurrence. Diabetes mellitus tended to increase (adjusted hazard ratio, 2.38; 95% confidence interval, 0.98-5.80; P=0.056), whereas treated hypertension tended to decrease (0.45, 0.20-1.01; P=0.054) the risk for fatal recurrent PICH. Previous ischemic stroke independent of confounding factors may increase the risk for PICH recurrence.


Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators.
Evidence from animal models convincingly supports the fact that gene therapy can be an advantageous strategy in the treatment of chronic destructive RA. In this article, we review the state of the art in anticytokine gene transfer into the synovial arthritic joint with the emphasis on IL-1Ra, IL-4, and IL-10 effects on CIA in mice. In CIA, only high and continuous release of IL-1Ra protein systemically by mini-osmotic pumps could prevent disease onset and was curative in mice. Local gene transfer seemed to be the obvious way to reach the high local levels that are demanded for protection. It was shown that local IL-1Ra overexpression reduced arthritis incidence and severity as well as tissue destruction. In line with observations about neutralizing antibodies and soluble receptors, gene therapy with TNF soluble receptors provided anti-inflammatory activity in early arthritis but not in advanced arthritis. The limited efficacy at later stages and poor protection against destruction imply that the combination of gene constructs for TNF and IL-1 inhibitors is the obvious direction for future therapy. Apart from targeting of proinflammatory cytokines, adenoviral overexpression of IL-10 and IL-4 may have therapeutic applicability. Local injection of AdIL-10 in the knee joint was effective at the site, but also highly reduced spreading to ipsilateral sites. High local dosages caused suppression in contralateral sites as well. The reports on the anti-inflammatory effect of AdIL-4 are conflicting; however, all present data showed that IL-4 overexpression provides impressive protection against cartilage and bone erosion. Apart from the local effects in the injected joint, it is becoming more and more clear that local treatment also affects arthritis in nearby joints. This is an intriguing general finding, which may enlarge the therapeutic applicability of gene transfer in human arthritis. Proving the feasibility of gene therapy in experimental arthritis, most research efforts are now focused on improving local gene delivery by enhanced viral infection of synovial cells, using RGD-modified adenovirus, or achieving prolonged persistence and regulated expression with AAV. Elegant future alternatives are the application of in vitro engineered T cells as a vehicle capable of specific homing to joint tissues. The feasibility of viral transduction of chondrocytes to obtain a tissue-specific approach to treat articular cartilage damage in arthritis needs further attention.


On the Detection of Overlapped Network Communities via Weight Redistributions.
A community is an important attribute of networking, since people who join networks tend to join communities. Community detection is used to identify and understand the structure and organization of real-world networks, thus, it has become a problem of considerable interest. The study of communities is highly related to network partitioning, which is defined as the division of a network into a set of groups of approximately equal sizes with minimum number of edges. Since this is an NP-hard problem, unconventional computation methods have been widely applied. This work addresses the problem of detecting overlapped communities (communities with common nodes) in weighted networks with irregular topologies. These communities are particularly interesting, firstly because they are more realistic, i.e., researchers may belong to more than one research community, and secondly, because they reveal hierarchies of communities: i.e., a medical community is subdivided into groups of certain specialties. Our strategy is based on weight redistribution: each node is examined against all communities and weights are redistributed between the edges. At the end of this process, these weights are compared to the total connectivity of each community, to determine if overlapping exists.


Native aortic valve infective endocarditis caused by Streptococcus agalactiae in a renal transplant recipient.
Infections with Streptococcus agalactiae or group B Streptococcus (GBS) are usually seen during pregnancy or in the neonatal period. The authors report a case of GBS aortic valve endocarditis in a renal transplant patient. GBS endocarditis is often aggressive despite appropriate therapy. The reported patient required prolonged antibiotics and valve replacement. To the authors' knowledge, this is the only reported case of GBS endocarditis in a renal transplant patient.


Enhancing the empiric antibiotic selection by introducing an antibiogram toolkit in a tertiary care hospital in Southern India - A prospective study.
Antibiograms gives an overview of the cumulative susceptibility of formal antibiotics to bacterial isolates, which reflects the portion of each bacterium susceptible to a given antibiotic formulation by using antimicrobial susceptibility testing. The objective of this study is to gather and analyse data from drug utilization evaluation (DUE) studies and antimicrobial susceptibility tests in order to create an antibiogram toolkit that will help clinicians to select appropriate antimicrobial agents for initial empirical antibiotic therapy at point of care settings and avoid irrational use of antibiotics. A prospective interventional study was conducted at tertiary care hospital, biological samples of infectious patients were collected from various wards as per Clinical & Laboratory Standards Institute CLSI M39-A4 guidelines. Antimicrobial susceptibility results were analysed using WHONET software. Antibiotic stewardship committee was formed and involved in monitoring the usage of antibiotics, measuring outcomes, collecting feedback and finding the scope for improving the application of antibiogram toolkit in the hospital. Antibiotic usage tracking method was followed to know the level of adherence to the prescribing guidelines by the health care professionals. A total of 157 samples were obtained from various wards of the hospital. In that, Escherichia coli, Staphylococcus aureus and Klebsiella Pneumoniae were isolated in significant numbers. Antibacterial susceptibility results were collected, an initial antibiogram was developed for 18 antibacterial agents with respect to 3 gram-positive (+) and 1 gram-negative (-) organisms. 90% of prescribers mentioned that the antibiogram was useful, and 76% of them adhered to the guidelines. 26% were not adhered due to the patient-related factors. In our study, we have used qualitative and quantitative evaluation of drug utilization (DUE) reports to understand the existing prescribing pattern of antibiotics and setting target organisms and antibacterials to develop the hospital antibiogram. Combining DUE studies and antibiogram development was helpful in implementing effective antibiotic policies for the hospital. Further, this study pattern will be continued on a yearly basis and focused on developing cumulative antibiograms to understand the changes in resistance pattern of antimicrobials and utilization of antibiotics in the hospital.


Tunable Magnetization Dynamics in Interfacially Modified Ni81Fe19/Pt Bilayer Thin Film Microstructures.
Interface modification for control of ultrafast magnetic properties using low-dose focused ion beam irradiation is demonstrated for bilayers of two technologically important materials: Ni81Fe19 and Pt. Magnetization dynamics were studied using an all-optical time-resolved magneto-optical Kerr microscopy method. Magnetization relaxation, precession, damping and the spatial coherence of magnetization dynamics were studied. Magnetization precession was fitted with a single-mode damped sinusoid to extract the Gilbert damping parameter. A systematic study of the damping parameter and frequency as a function of irradiation dose varying from 0 to 3.3 pC/μm(2) shows a complex dependence upon ion beam dose. This is interpreted in terms of both intrinsic effects and extrinsic two-magnon scattering effects resulting from the expansion of the interfacial region and the creation of a compositionally graded alloy. The results suggest a new direction for the control of precessional magnetization dynamics, and open the opportunity to optimize high-speed magnetic devices.


Diversity of Salmonella enterica serovar Typhi strains collected from india using variable number tandem repeat (VNTR)-PCR analysis.
Typhoid fever is endemic in India, and a seasonal increase of cases is observed annually. In spite of effective therapies and the availability of vaccines, morbidity is widespread owing to the circulation of multiple genetic variants, frequent migration of asymptomatic carriers, unhygienic food practices and the emergence of multidrug resistance and thus continues to be a major public health problem in developing countries, particularly in India. Classical methods of strain typing such as pulsed-field gel electrophoresis, ribotyping, random amplification of polymorphic DNA and amplified fragment length polymorphism are either laborious and technically complicated or less discriminatory. We investigated the molecular diversity of Indian strains of Salmonella enterica serovar Typhi (S. Typhi) isolated from humans from different parts of India to establish the molecular epidemiology of the organism using the variable number tandem repeat (VNTR)-PCR analysis. The electrophoretic band pattern was analysed using the GelCompar II software program. Of the 94 strains tested for three VNTRs loci, 75 VNTR genotypes were obtained. Of the three VNTRs tested in this study, VNTR1 was amplified in all the strains except one and found to be predominant. VNTR2 was amplified only in 57 strains with a Simpson diversity index of 0.93 indicating the high variability of this region within the strains. VNTR3 was amplified in 90 strains. The discriminatory power of this typing tool has been greatly enhanced by this VNTR2 region as the other two regions could not discriminate strains significantly. In our study, about 55 % of the strains amplified all three VNTR regions and 39 % of the strains lacked the VNTR2 region. Among the three VNTR regions tested, the majority of the strains produced similar banding pattern for any two regions grouped into a cluster. The strains grouped as a genotype were from the same geographical location. Strains collected from each geographical region were also highly heterogeneous. Such analysis is important to identify the genetic clones of the pathogen associated with sporadic infections and disease outbreak to identify the common source and implement public health measures.


Mononuclear leucocyte chemotaxis in Boyden chambers: inhibition by subantimitotic concentrations of antitubulins.
The chemotaxis of Lymphoprep -isolated human mononuclear leucocytes (L-MNs) from peripheral blood was inhibited by subantimitotic concentrations of the antitubulins demecolcine, podophyllic acid ethylhydrazide, vinblastine and griseofulvin. It is suggest that L-MN chemotaxis, like polymorphonuclear leucocyte (PMN) chemotaxis, is composed of a direct antitubulin-insensitive chemotaxis and a leukocyte-induced antitubulin-sensitive chemotaxis.


Improving the quality of hemodialysis treatment: a community-based randomized controlled trial to overcome patient-specific barriers.
Mortality rates among US hemodialysis patients are the highest in the industrialized world at 23% per year. Measures of dialysis dose (Kt/V) correspond strongly with survival and are inadequate in one sixth of patients. Inadequate dialysis is also associated with increased hospitalizations and high inpatient costs. Our previous work identified 3 barriers to adequate hemodialysis: dialysis underprescription, catheter use, and shortened treatment time. To determine the effect of a tailored intervention on adequacy of hemodialysis. Community-based randomized controlled trial with recruitment from April 1999 to June 2000 at 29 hemodialysis facilities in northeast Ohio. Forty-four nephrologists and their 169 randomly selected adult patients receiving inadequate hemodialysis. Nephrologists were randomly assigned to an intervention (n = 21) or control (n = 23) group. For patients in the intervention group (n = 85), depending on the barrier(s) present, a study coordinator gave nephrologists recommendations about optimizing dialysis prescriptions, expedited conversion of catheters to surgically created grafts or fistulas, and educated patients about the importance of compliance with treatment time. Patients in the control group (n = 84) continued to receive usual care. Changes in Kt/V and specific barriers after 6 months. At baseline, intervention and control patients had similar Kt/V measurements, specific barriers, and demographic and medical characteristics. After 6 months, intervention patients had 2-fold larger increases in Kt/V compared with control patients (+0.20 vs +0.10; P<.001) and were more likely to achieve their facility Kt/V goal (62% vs 42%; P =.01). Intervention patients also had nearly 3-fold larger increases in dialysis prescription (+0.16 vs +0.06; P<.001) and were 4 times more likely to change from use of catheters to use of fistulas/grafts (28% vs 7%; P =.04). An intervention tailored to patient-specific barriers resulted in increased hemodialysis dose. Extending this approach to the 33 000 persons in the United States receiving inadequate hemodialysis may substantially enhance patient survival, diminish hospitalizations, and decrease inpatient expenditures.


Formate and its role in amino acid metabolism.
The aim of this report is to examine critical relationships between amino acid and formate metabolism with particular reference to the production of formate, and to review novel functions of formate. In addition to well established mechanisms in one-carbon metabolism, formate may play an important role in early pregnancy by preventing the onset of neural tube defects in sensitive strains of mice, including mice with deficiencies in MTHFD1L, the glycine cleavage system and the mitochondrial folate transporter. Markedly elevated, circulating levels of formate are found in late pregnancy, including in cord blood, as well as elevated levels of amino acid precursors. These are consistent with specific roles for formate in late pregnancy. Serine metabolism may reduce NADP to NADPH and permit the use of NADPH in reductive reactions. Novel, noncanonical functions of formate include high rates of formate production from serine in cells and in cancers. Novel, noncanonical functions of formate continue to be discovered. Integrating their functions with well established elements of one-carbon metabolism remains an important future objective.


Constructing of efficient interface solar evaporator: In-situ colloid foaming strategy for solar desalination and visible light response sewage purification.
The shortage of drinking water has become a global problem, coastal cities can make full use of abundant seawater resources by desalination technology to ease the contradiction between supply and demand. However, fossil energy consumption contradicts the goal of reducing carbon dioxide emissions. Currently, researchers favor interfacial solar desalination devices relying only on clean solar energy. Based on the structure optimization of the evaporator, a kind of device composed of a superhydrophobic BiOI (BiOI-FD) floating layer and CuO polyurethane sponge (CuO sponge) is constructed in this paper, with its design advantages presented in the following two aspects: 1. The novel BiOI-FD photocatalyst in the floating layer reduces the surface tension and realizes the degradation of the enriched pollutants, ensuring the device to achieve solar desalination and inland sewage purification; 2. CuO sponge can inhibit salt crystallization and realize the combination of the water transport and photothermal layers. Particularly, the photothermal evaporation rate of the interface device reached 2.37 kg m-2 h-1.The novel interface evaporator design will bring a new solution for solar desalination, sewage treatment and large-scale application.


[Localization of specific antigen in the organs of newborn animals vaccinated with liver smallpox vaccine].
Of 20 suckling rabbits, 4-5-days old, inoculated with live smallpox vaccine intradermally 6 displayed symptoms of generalized pox virus and neuroparalysis complications. Intensive accumulation of specific antigen in the brain, lungs, spleen, and the lymph glands was revealed by immunofluorescent method. The smallpox vaccine virus was isolated from these organs. Prolonged persistance of the attenuated smallpox virus was observed in the brain, spinal cord, lungs, spleen, and the lymph glands of 14 suckling rabbits showing no signs of any disease; specific antigen was revealed by immunofluorescent test. Vascular disturbances and slight cell changes were observed in the brain tissue of the inoculated animals. These changes were more severe in the sick animals.


Microwave biochar produced with activated carbon catalyst: Characterization and adsorption of heavy metals.
Novel microwave biochar derived from wheat straw (WS) using a range of power levels, with activated carbon catalyst as microwave absorber, was produced, characterized and tested as adsorbent of three heavy metals (Pb2+, Cd2+, and Cu2+). The microwave biochar with the greatest specific surface area (156.09 m2 g-1) and total pore volume (0.0790 cm3 g-1) were produced at 600 W (WS600) and 500 W (WS500) power level, respectively. Maximum adsorption capacities of WS500 to Pb2+, Cd2+ and Cu2+ were 139.44 mg g-1, 52.92 mg g-1, and 31.25 mg g-1, respectively. Optimal pH value for heavy metal removal was at range of 5-6, and Pb2+ showed the strongest affinity in competitive adsorption experiments. The adsorption data were fitted better by pseudo-second-order model and Langmuir isotherm, indicating that adsorption process was mainly explained by monolayer adsorption, and chemical adsorption occupied important role. The predominant adsorption mechanisms of heavy metals on microwave pyrolysis biochar included complexation with oxygen-containing functional groups (i.e., carboxylic acid CO and -OH) and precipitation with carbonate. In addition, reused WS600 maintained 76.17% and 96.07% of their initial adsorption capacity for Cu2+ and Cd2+, respectively. These results suggest that microwave biochar produced with activated carbon catalyst has excellent potential for efficient use in the removal of heavy metals from waste water.


Changes in structure of alpha 2-macroglobulin upon reaction with trypsin as assessed by light scattering and differential scanning calorimetry.
Employing a combination of static and dynamic light scattering, as well as differential scanning calorimetry (DSC), the structural changes which appear in alpha 2-macroglobulin (alpha 2M) upon trypsin binding have been further characterized. Light-scattering measurements suggest that a 15% reduction in both the hydrodynamic radius and radius of gyration occurs when two molecules of trypsin complex to alpha 2M. Approx. 85% of this trypsin-induced compaction results from the binding of the first proteinase. A complementary result was obtained from DSC measurements in which the major fraction of the trypsin-induced conversion of alpha 2M to a single more thermally stable form results from interaction with the first proteinase molecule. These observations support a functionally asymmetric model of trypsin binding to alpha 2M in which the significant reduction in size of the complex is primarily due to the initial interaction of alpha 2M with a single proteinase molecule.


Kidney Function and Cognitive Decline in Older Adults: Examining the Role of Neurodegeneration.
Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta-amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association. Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT). Thirteen memory centers (France and Monaco, 2008-2016). A total of 1,334 community-dwellers >70 years old without dementia at baseline. We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD-Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z-score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z-score using mixed-effect models and (2) progression on CDR using Cox models and mixed-effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta-amyloid (measured with positron emission tomography). Median (IQR) eGFR was 73(60-84) mL/min/1.73 m2 . Two hundred sixty-nine participants experienced progression on CDR score during follow-up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01-1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z-score (adjusted β-coefficient -0.004, 95% CI -0.014; 0.006). Associations were not modified after further adjustment for beta-amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270). We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.


Quantitative assessment of EF-1alpha.GTP binding to aminoacyl-tRNAs, aminoacyl-viral RNA, and tRNA shows close correspondence to the RNA binding properties of EF-Tu.
A ribonuclease protection assay was used to determine the equilibrium dissociation constants (Kd) for the binding of various RNAs by wheat germ EF-1alpha.GTP. Aminoacylated fully modified tRNAs and unmodified tRNA transcripts of four specificities (valyl, methionyl, alanyl, and phenylalanyl) from higher plants or Escherichia coli were bound with Kd values between 0.8 and 10 nM. A valylated 3'-fragment of turnip yellow mosaic virus RNA, which has a pseudoknotted amino acid acceptor stem, was bound with affinity similar to that of Val-tRNAVal. Uncharged tRNA and initiator Met-tRNAMet from wheat germ, RNAs that are normally excluded from the ribosomal A site in vivo, bound weakly. The discrimination against wheat germ initiator Met-tRNAMet was almost entirely due to the 2'-phosphoribosyl modification at nucleotide G64, since removal resulted in tight binding by EF-1alpha.GTP. A 44-nucleotide RNA representing a kinked acceptor/T arm obtained by in vitro selection to bacterial EF-Tu formed an Ala-RNA.EF-1alpha.GTP complex with a Kd of 29 nM, indicating that much of the binding affinity for aminoacylated tRNA is derived from interaction with the acceptor/T half of the molecule. The pattern of tRNA interaction observed for EF-1alpha (eEF1A) therefore closely resembles that of bacterial EF-Tu (EF1A).


Involvement of CacyBP/SIP in differentiation and the immune response of HaCaT keratinocytes.
CacyBP/SIP is a multifunctional protein present in various cells and tissues. However, its expression and role in the epidermis has not been explored so far. In this work, using RT-qPCR, Western blot analysis and three-dimensional (3D) organotypic cultures of HaCaT keratinocytes we show that CacyBP/SIP is present in the epidermis. To investigate the possible role of CacyBP/SIP in keratinocytes we obtained CacyBP/SIP knockdown cells and studied the effect of CacyBP/SIP deficiency on their differentiation and response to viral infection. We found that CacyBP/SIP knockdown results in reduced expression of epidermal differentiation markers in both undifferentiated and differentiated HaCaT cells. Since epidermis is engaged in immune defense, the impact of CacyBP/SIP knockdown on this process was also analyzed. By applying RT-qPCR and Western blot it was found that poly(I:C), a synthetic analog of double-stranded RNA that mimics viral infection, stimulated the expression of genes involved in antiviral response, such as IFIT1, IFIT2 and OASL. Interestingly, following poly(I:C) stimulation, the level of expression of these genes was significantly lower in cells with CacyBP/SIP knockdown than control ones. Since the signaling pathway mediating cellular responses to viral infection involves, among others, the STAT1 transcription factor, we measured its activity using luciferase assay and found that it was lower in CacyBP/SIP knockdown HaCaT cells. Altogether, the presented results indicate that CacyBP/SIP promotes epidermal differentiation and might be involved in response of the skin cells to viral infection.


Interleukin-10 in cancer immunotherapy: from bench to bedside.
Interleukin (IL)-10 was one of the first cytokines to be recognized. However, its functionality in promoting antitumor immunity was described more recently. Context- and concentration-dependent biological effects are the hallmarks of the pleiotropic role of IL-10. Despite reducing tumor-promoting inflammation, IL-10 may have a role in rejuvenating exhausted tumor-resident T cells. Contrary to the assumption that IL-10 produces an immunosuppressive tumor microenvironment (TME), it promotes activation of tumor-resident CD8+ T cells, which aids tumor rejection. Emerging data from published early-Phase trials have shown mixed results in different tumor types. In this review, we summarize the biological effects of IL-10 and highlight the clinical experience using pegilodecakin.


Maternal depression, parental attributions, and adolescent psychopathology: An evaluation using observational and video-mediated recall methods.
Parenting styles associated with maternal depression are a risk factor for adolescent psychopathology, and maternal attributional styles may be a key mechanism in this relationship. Mother-adolescent dyads (N = 180; 96 male; ages 10-15) completed in-person interactions and then the mothers participated in a video-mediated recall procedure to assess maternal attributions. Maternal depression was associated with negative attributions. Negative attributions were associated with low parental acceptance, aggressive parenting, and low positive parenting. Positive maternal attributions were associated with less aggressive parenting, and more positive parenting during one interaction task. Adolescent externalizing behaviors were associated with negative attributions. Future research should evaluate whether maternal attributions mediate the association between maternal depression and both parenting behaviors and adolescent mental health.


Crystal structures of main protease (Mpro) mutants of SARS-CoV-2 variants bound to PF-07304814.
There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (Mpro) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 Mpro with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 Mpro. However, the binding modes of PF-07304814 with Mpros from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six Mpro mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to Mpro mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant Mpros. Patterns for PF-07304814 to bind with these investigated Mpro mutants and the wild-type Mpro are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of Mpro mutants when bound to an inhibitor.


Retrospective analysis of neonatal deaths secondary to infections in England and Wales, 2013-2015.
To estimate the overall and infection-related neonatal mortality rate and the pathogens responsible using electronic death registrations. Retrospective analysis of national electronic death registrations data. England and Wales. Neonates aged <28 days. Overall and infection-related mortality rate per 1000 live births in term, preterm (28-36 weeks) and extremely preterm (<28 weeks) neonates; the contribution of infections and specific pathogens; comparison with mortality rates in 2003-2005. The neonatal mortality rate during 2013-2015 (2.4/1000 live births; 5095 deaths) was 31% lower than in 2003-2005 (3.5/1000; 6700 deaths). Infection-related neonatal mortality rate in 2013-2015 (0.32/1000; n=669) was 20% lower compared with 2003-2015 (0.40/1000; n=768), respectively. Infections were responsible for 13.1% (669/5095) of neonatal deaths during 2013-2015 and 11.5% (768/6700) during 2003-2005. Of the infection-related deaths, 44.2% (296/669) were in term, 19.9% (133/669) preterm and 35.9% (240/669) extremely preterm neonates. Compared with term infants (0.15/1000 live births), infection-related mortality rate was 5.9-fold (95% CI 4.7 to 7.2) higher in preterm (0.90/1000) and 188-fold (95% CI 157 to 223) higher in extremely preterm infants (28.7/1000) during 2013-2015. A pathogen was recorded in 448 (67%) registrations: 400 (89.3%) were bacterial, 37 (8.3%) viral and 11 (2.4%) fungal. Group B streptococcus (GBS) was reported in 30.4% (49/161) of records that specified a bacterial infection and 7.3% (49/669) of infection-related deaths. Overall and infection-related neonatal mortality rates have declined, but the contribution of infection and of specific pathogens has not changed. Further preventive measures, including antenatal GBS vaccine may be required to prevent the single most common cause of infection-related deaths in neonates.


Electronically excited state generation during the reaction of p-benzoquinone with H2O2. Relation to product formation: 2-OH- and 2,3-epoxy-p-benzoquinone. The effect of glutathione.
The reaction between H2O2 and p-benzoquinone proceeds with consumption of both reactants with second order rate constants of 1.66- and 0.77 M-1S-1, respectively. The process is mainly supported by oxygen addition reactions to the quinone resulting in the formation of both 2,3-epoxy-p-benzoquinone and 2-OH-p-benzoquinone. The former product accumulates in the assay mixture without participating in further reactions. The formation of the latter product implies free radical intermediates such as 2-OH-p-benzosemiquinone anion, which supports the generation of electronically excited states upon its oxidation by H2O2, presumably as part of an organic Fenton reaction. The relaxation of the excited state is accompanied by photoemission at 485-530 nm. Glutathione was found to counteract the oxidative aspects of the reaction between p-benzoquinone and H2O2 by a series of processes involving (a) a rapid reductive addition to the quinone with formation of a substituted p-benzohydroquinone; (b) an effective quenching of photoemission, which might be attributed to the deactivation of the excited state by the p-benzohydroquinone-glutathione adduct, and (c) the decomposition of the formed 2,3-epoxy-p-benzoquinone, also by reductive cleavage of the epoxide ring.


Effects of SQ 14,225, an orally active inhibitor of angiotensin-converting enzyme on blood pressure, heart rate and plasma renin activity of conscious normotensive dogs.
Oral administration of SQ 14,225 (0.03--3 mg/kg) to conscious normotensive dogs caused inhibition of the pressor response to intravenously administered angiotensin I (AI), the duration of which was dose-dependent. All doses of 0.1 mg/kg or greater caused 85--95% inhibition 30 min after administration whereas 0.03 mg/kg produced only a 25% inhibition. Pressor responses to angiotensin II (AII) were not similarly inhibited. Blood pressure was moderately reduced in a dose-related manner and followed the same pattern as inhibition of the AI pressor responses. The maximum change occurred after 1.0 mg/kg with only a more rapid onset occurring after the 3.0 mg/kg dose. Heart rate was not appreciably changed. SQ 14,225 also increased plasma renin activity (PRA), the levels and duration of which were dose-related. These data indicate that SQ 14,225 is an orally effective, potent inhibitor of angiotensin I-converting enzyme (ACE) in dogs. It appears that in mongrel dogs, ACE inhibition results in a slight to moderate reduction in blood pressure and an increase in PRA.


Chorioretinitis of the newborn with herpes simplex virus type 1. Report of a case.
A disseminated herpes simplex virus (HSV) infection involving the central nervous system and accompanied by chrioretinitis in a a 3-week-old girl is described. The aetiologic diagnosis was established on the basis of vrius isolated from skin vesicles, and a significant rise in complement fixing antibodies to HSV type 1. The mode of transmission of the virus to the infant apparently was direct contact with an oral lesion in the mother, that was present at the time of delivery. The patient survived but became blind and microcephalic, with severe neurological sequelae. The virus isolated was identified as HSV type 1, which is an infrequent finding in herpetic chorioretinitis of the newborn.


Chemotherapy-related cardiac dysfunction: the usefulness of myocardial work indices.
The role of left ventricular global longitudinal strain (GLS) in the diagnosis of subclinical cardiac damage induced by anticancer drugs is now consolidated. Considering some strain disadvantages such as the dependence on the haemodynamic loading conditions, the aim of our study was to investigate the usefulness of non-invasive myocardial work indices (MWI) derived from pressure-strain analysis, in the early diagnosis of cardiotoxicity. We enrolled 61 consecutive patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy followed by taxane + trastuzumab. Patients underwent a cardiological evaluation with 2D echocardiography including measurement of the left ventricular ejection fraction (LVEF) and other conventional parameters of systolic and diastolic function, GLS and MWI at baseline (T0), 3 months (T1) and 6 months (T2) after starting chemotherapy. At T1 and T2, we did not find a significant reduction in LVEF but we found a significant reduction in GLS and MWI (p value < 0.05). In addition, at T2, 31% of patients developed subclinical cardiac dysfunction defined as a relative decrease ≥ 12% of GLS from baseline. Global work index (GWI), global constructive work (GCW) and global work efficiency (GWE) decreased significantly in both patients with subclinical dysfunction and in those without subclinical dysfunction (p value < 0.05). Patients with subclinical dysfunction at T2 showed lower values of GCW at T0. MWI changed significantly during chemotherapy and appeared to alter precociously compared to GLS. Therefore, a multiparametric approach including left ventricular GLS and MWI measurements should be used in the evaluation of patients undergoing cardiotoxic antineoplastic treatment.


Seronegative spondylarthropathy without spine involvement in Behçet's syndrome.
The case of a 49-year-old man affected by Behçet's syndrome (BS) without any clinical or radiological evidence of ankylosing spondylitis, exhibiting a peripheral enthesitis typical of seronegative spondyloarthropathy (SpA) is reported. The diagnosis of SpA is supported by computed tomographic evidence of sacroiliitis. This case confirms our hypothesis that patients with BS may have other forms of SpA than AS.


Dual chemotherapy with benznidazole at suboptimal dose plus curcumin nanoparticles mitigates Trypanosoma cruzi-elicited chronic cardiomyopathy.
Curcumin (Cur) is a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa. Its anti-inflammatory and cardioprotective properties are increasingly considered to have beneficial effects on the progression of cardiomyopathy associated with Chagas disease, caused by Trypanosoma cruzi. However, the Cur therapeutic limitation is its bioavailability and new Cur nanomedicine formulations are developed to overcome this obstacle. In this research, we provide evidence showing that oral therapy with a suboptimal dose of the standard parasiticidal drug benznidazole (BZ) in combination with Cur-loaded nanoparticles is capable of reducing myocardial parasite load, cardiac hypertrophy, inflammation and fibrosis in mice with long-term infection by T. cruzi. Treatment with BZ plus Cur was highly effective in downregulating myocardial expression of proinflammatory cytokines/chemokines (IL-1β, TNF-α, IL-6, CCL5), and the level/activity of matrix metalloproteinases (MMP-2, MMP-9) and inducible enzymes (cyclooxygenase, nitric oxide synthase) implicated in leukocyte recruitment and cardiac remodeling. Oral administration of a Cur-based nanoformulation displays potential as a complementary strategy to the conventional BZ chemotherapy in the treatment of chronic Chagas heart disease.


Value of Plasma Methylated SFRP2 in Prognosis of Gastric Cancer.
Secreted frizzled-related protein 2 (SFRP2) in circulating tumor DNA (ctDNA) is related to gastric cancer (GC) proliferation. However, whether methylated SFRP2 in ctDNA serves as the biomarker in GC patients remains unknown. To investigate the relationship between methylated SFRP2 and the clinical outcomes of GC patients. One hundred and forty-eight GC patients receiving systemic chemotherapy were collected during 2015-2017. Aberrant SFRP2 methylation was detected before and after chemotherapy by digital PCR-based technologies. Baseline SFRP2 methylation positively correlated with lymph node status (P < 0.001), distant metastasis (P < 0.001) and TNM stage (P = 0.005). The top 50% methylated SFRP2 had shorter progression-free survival (PFS) and overall survival (OS) than those with bottom 50% in stage III GC patients (median PFS, 11.0 vs. NR months; HR 13.05; 95% CI 3.05-55.95; median OS 17.0 vs. NR months; HR 7.80; 95% CI 1.81-33.60) and stage IV GC patients (median PFS, 4.0 vs. 7.0 months; HR 2.74; 95% CI 1.58-4.78; median OS 12.0 vs. 16.0 months; HR 3.14; 95% CI 1.67-5.92). Besides, the increased methylated SFPR2 from baseline to post-treatment was related to the worse PFS and OS among stage IV patients (median PFS, 5.0 vs. 7.0 months; HR 2.17; 95% CI 1.25-3.76; median OS 12.0 vs. 15.5 months; HR 3.51; 95% CI 1.94-6.35), but not to stage III patients. SFRP2 methylation and dynamic change are associated with GC prognosis. Our findings provide potential biomarker detection approach in ctDNA for prognosis prediction and dynamic monitoring among GC patients.