Persistent abnormalities in pulmonary arterial compliance after heart transplantation in patients with combined post-capillary and pre-capillary pulmonary hypertension.
The hemodynamic definitions of pulmonary hypertension (PH) in left heart disease have recently been refined to better match the characteristics required to reflect the presence of pulmonary vascular disease. Accordingly, we tested the hypothesis that abnormalities in the stiffness of pulmonary circulation would persist after heart transplantation in patients with combined post-capillary and pre-capillary PH (Cpc-PH) in contrast to those with isolated post-capillary PH (Ipc-PH). We retrospectively analyzed right heart hemodynamics in a cohort of 295 consecutive patients with heart failure and advanced left ventricular systolic dysfunction (LVSD) before and 1 year after heart transplantation. According to their baseline hemodynamic profile, patients were classified as: 75 Cpc-PH, 111 Ipc-PH, and 98 without PH (no-PH), and 11 pre-capillary PH. One year after heart transplantation, pulmonary artery pressures, pulmonary vascular resistance and cardiac index normalized in all patients regardless of the baseline hemodynamic profile. However, pulmonary arterial compliance remained lower in Cpc-PH patients (from 1.6±1.2 at baseline to 3.7±1.4 ml/mmHg at 1 year) than in Ipc-PH (from 1.2±2.0 to 4.4±2.3 ml/mmHg) and no-PH patients (from 3.7±2.0 to 4.5±1.8 ml/mmHg); (adjusted p = 0.03 Ipc-PH vs. Cpc-PH INT<0.001). In heart failure patients with advanced LVSD, a hemodynamic profile characterized by Cpc-PH predicts the persistence of a stiffer pulmonary circulation at 1 year after heart transplantation.


Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch.
Flow cytometric crossmatching (FCXM) and panel reactive antibody (PRA) screening techniques are more sensitive than anti-human globulin enhanced cytotoxicity (AHG-CDC) techniques at detecting anti-HLA antibodies. The clinical significance of a positive FCXM in primary renal transplant recipients with a negative AHG-CDC crossmatch is unclear. We performed retrospective FCXM and flow cytometric panel reactive antibody (FlowPRA) determinations in primary renal transplant recipients with a negative T cell AHG-CDC crossmatch and a negative B cell CDC crossmatch pretransplant. Eighteen (13%) of 143 patients exhibited a positive retrospective T cell FCXM. Of these patients, six (33%) experienced early graft loss with explant histology, demonstrating antibody-mediated rejection in five of six cases. The 12 patients with positive T cell FCXM who maintained their grafts experienced more adverse events posttransplant, including more early, steroid-resistant, and recurrent rejection. Furthermore, in a subgroup of patients undergoing protocol biopsies, those with a positive T cell FCXM exhibited more subclinical rejection. Anti-HLA antibodies were detected by FlowPRA in all 18 patients with a positive T cell FCXM, whereas AHG-CDC PRA detected antibodies in only 8 of 18 patients. Therefore, flow cytometric techniques identify sensitized primary renal transplant recipients undetected by AHG-CDC techniques. In those patients, a positive T cell FCXM is associated with an increased risk of early graft loss due to antibody-mediated rejection and may represent a relative contraindication to transplantation. Moreover, those patients are also at increased risk of severe and recurrent rejection, which may carry implications for long-term graft outcomes.


Advances in the integration of transcriptional regulatory information into genome-scale metabolic models.
A major goal of systems biology is to build predictive computational models of cellular metabolism. Availability of complete genome sequences and wealth of legacy biochemical information has led to the reconstruction of genome-scale metabolic networks in the last 15 years for several organisms across the three domains of life. Due to paucity of information on kinetic parameters associated with metabolic reactions, the constraint-based modelling approach, flux balance analysis (FBA), has proved to be a vital alternative to investigate the capabilities of reconstructed metabolic networks. In parallel, advent of high-throughput technologies has led to the generation of massive amounts of omics data on transcriptional regulation comprising mRNA transcript levels and genome-wide binding profile of transcriptional regulators. A frontier area in metabolic systems biology has been the development of methods to integrate the available transcriptional regulatory information into constraint-based models of reconstructed metabolic networks in order to increase the predictive capabilities of computational models and understand the regulation of cellular metabolism. Here, we review the existing methods to integrate transcriptional regulatory information into constraint-based models of metabolic networks.


[The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro].
To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC(50) greater than 200 μg·m L(-1). DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1(IIIB,) HIV-1(74V,) HIV-1(RF/V82F/184V,) HIV-1(NL4-3) (gp41(36G)N42S,) HIV-1(KM018,) HIV-1(TC-1) and HIV-1(Wan.) However, NNRTIs drug-resistant strain HIV-1(A17) showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.


Dose dependency of adjuvant activity of particulate matter from five European sites in three seasons in an ovalbumin-mouse model.
Various particulate matter (PM) samples were tested for their adjuvant potency in an animal model of allergy (ovalbumin) in the European Union study entitled Respiratory Allergy and Inflammation Due to Ambient Particles. Coarse and fine ambient particles were collected during spring, summer, and winter in Rome, Oslo, Lodz, Amsterdam, and De Zilk. De Zilk, at the Dutch seaside, has mainly westerly winds and served as a negative pollution control. EHC-93 (Ottawa dust) was used as a positive control. We studied the adjuvant potency of the particle antibody responses to ovalbumin and histopathological changes in the lung. After a sensitization phase by coexposure to EHC-93 and ovalbumin, the antibody response to ovalbumin and inflammatory responses in the lung were huge. There was more adjuvant activity in reaction to 9-mg/ml samples than to 3-mg/ml samples. A best-fit analysis of these samples shows that the ambient coarse and fine particles at these sites, in combination with allergens, have severe to mild adjuvant activity in the order Lodz, Rome, Oslo, and Amsterdam. A high dose of the fine fraction was more potent than a high dose of the coarse fraction, except at De Zilk, where the reverse was true. Spring and winter PM was more potent than summer PM. Depending on the site, either a water-soluble or a water-insoluble fraction was responsible for the adjuvant activity. A concentration of 3 mg/ml is effective for screening high-activity samples, as is a concentration of 9 mg/ml for screening low-activity samples in the ovalbumin-mouse model.


Small-period long-period fiber grating with improved refractive index sensitivity and dual-parameter sensing ability.
We UV inscribe and characterize a long-period fiber grating with a period of 25 μm. A series of polarization-dependent dual-peak pairs can be seen in the transmission spectrum, even though only the symmetrical refractive index modification is introduced. The fabricated grating exhibits a lower temperature sensitivity compared with standard long-period gratings and an enhanced refractive index sensitivity of ∼312.5 nm/RIU averaged from 1.315 to 1.395, which is more than four-fold higher than standard long-period gratings in this range. The full width at half-maximum of the fabricated grating is only about 0.6 nm, allowing for high-resolution sensing. Moreover, the grating period is so small that the attenuation dip corresponding to a high-order Bragg resonance can also be seen, which can act as a monitor of the unwanted perturbation to realize dual-parameter sensing.


Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules: A Randomized Clinical Trial.
Approximately 20% of thyroid nodules display indeterminate cytology. Molecular testing can refine the risk of malignancy and reduce the need for diagnostic hemithyroidectomy. To compare the diagnostic performance between an RNA test (Afirma genomic sequencing classifier) and DNA-RNA test (ThyroSeq v3 multigene genomic classifier). This parallel randomized clinical trial of monthly block randomization included patients in the UCLA Health system who underwent thyroid biopsy from August 2017 to January 2020 with indeterminate cytology (Bethesda System for Reporting Thyroid Cytopathology category III or IV). Molecular testing with the RNA test or DNA-RNA test. Diagnostic test performance of the RNA test compared with the DNA-RNA test. The secondary outcome was comparison of test performance with prior versions of the molecular tests. Of 2368 patients, 397 were eligible for inclusion based on indeterminate cytology, and 346 (median [interquartile range] age, 55 [44-67] years; 266 [76.9%] women) were randomized to 1 of the 2 tests. In the total cohort assessed for eligibility, 3140 thyroid nodules were assessed, and 427 (13.6%) nodules were cytologically indeterminate. The prevalence of malignancy was 20% among indeterminate nodules. The benign call rate was 53% (95% CI, 47%-61%) for the RNA test and 61% (95% CI, 53%-68%) for the DNA-RNA test. The specificities of the RNA test and DNA-RNA test were 80% (95% CI, 72%-86%) and 85% (95% CI, 77%-91%), respectively (P = .33); the positive predictive values (PPV) of the RNA test and DNA-RNA test were 53% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33). The RNA test exhibited a higher PPV compared with the prior test version (Afirma gene expression classifier) (54% [95% CI, 40%-67%] vs 38% [95% CI, 27%-48%]; P = .01). The DNA-RNA test had no statistically significant difference in PPV compared with its prior version (ThyroSeq v2 next-generation sequencing) (63% [95% CI, 48%-77%] vs 58% [95% CI, 43%-73%]; P = .75). Diagnostic thyroidectomy was avoided in 87 (51%) patients tested with the RNA test and 83 (49%) patients tested with the DNA-RNA test. Surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up. Both the RNA test and DNA-RNA test displayed high specificity and allowed 49% of patients with indeterminate nodules to avoid diagnostic surgery. Although previous trials demonstrated that the prior version of the DNA-RNA test was more specific than the prior version of the RNA test, the current molecular test techniques have no statistically significant difference in performance. ClinicalTrials.gov Identifier: NCT02681328.


Dietary indigestible components exert different regional effects on luminal mucin secretion through their bulk-forming property and fermentability.
The purpose of this study was to examine the effects of dietary indigestible components on mucin secretion in the respective parts of the gastrointestinal tract through their physico-chemical properties. Rats were fed either a control diet or diets containing 5% polystyrene foam (PSF), 5% fructooligosaccharide (FOS), 5% PSF + 5% FOS, or 10% beet fiber for 10 d. Mucins in the small intestine and feces were greater in the PSF, PSF + FOS, and beet fiber groups than in the control and FOS groups. In the cecum, greater mucins were observed in the FOS, PSF + FOS, and beet fiber groups than in the control and PSF groups. None of the dietary treatment was effective on gastric mucins. Cecal mucins were significantly correlated with the cecal pool sizes of total short-chain fatty acids. The correlation between fecal mucins and fecal numbers was also significant. The results suggest that the effect of the bulk-forming property of the dietary indigestible component on mucin secretion is limited to the duct, while fermentability is effective only in the cecum.


Pattern of DNA increase in macronuclear anlagen of Tetrahymena.
By combining cytophotometry with autoradiography, five stages of macronuclear anlagen can be discriminated by their DNA content until the end of the first cell cycle after conjugation in Tetrahymena. DNA increases from 2C to about 32C. Each S-phase is followed by a non-synthetic period. Comparing the mean nuclear DNA content after and before each S-phase revealed that 16C anlagen contain significantly less DNA than twice the amount of 8C anlagen. This is unlike the situation in other S-phases during which the amount of DNA is precisely doubled. In the second cell cycle after conjugation some of the cells increase their macronuclear G2 DNA content beyond the 64C stage, while the majority show a mean G2 content of about 64C.


Inhibition of tumor angiogenesis mediated by cartilage.
Capillary proliferation induced by tumor is shown to be inhibited by neonatal scapular cartilage. Using the rabbit cornea as an assay, the cartilage implant decreased the rate of capillary growth, induced by tumor, by an average of 75%. Vascularization was prevented completely in 28% of tumors. The inhibitory effect of small cartilage implants operates over distances of up to 2.0 mm and displays a gradient from the cartilage source. The experiments suggest that the cartilage inhibitor does not antagonize tumor angiogenesis factor, but appears to inhibit capillary proliferation directly. The inhibitory material does not elicit an inflammatory response in either the rabbit cornea or in the chick chorioallantoic membrane. Thus with further purification, it may prove useful as a means of maintining tumor dormancy by "antiangiogenesis."


Extended-range statistical ENSO prediction through operator-theoretic techniques for nonlinear dynamics.
Forecasting the El Niño-Southern Oscillation (ENSO) has been a subject of vigorous research due to the important role of the phenomenon in climate dynamics and its worldwide socioeconomic impacts. Over the past decades, numerous models for ENSO prediction have been developed, among which statistical models approximating ENSO evolution by linear dynamics have received significant attention owing to their simplicity and comparable forecast skill to first-principles models at short lead times. Yet, due to highly nonlinear and chaotic dynamics (particularly during ENSO initiation), such models have limited skill for longer-term forecasts beyond half a year. To resolve this limitation, here we employ a new nonparametric statistical approach based on analog forecasting, called kernel analog forecasting (KAF), which avoids assumptions on the underlying dynamics through the use of nonlinear kernel methods for machine learning and dimension reduction of high-dimensional datasets. Through a rigorous connection with Koopman operator theory for dynamical systems, KAF yields statistically optimal predictions of future ENSO states as conditional expectations, given noisy and potentially incomplete data at forecast initialization. Here, using industrial-era Indo-Pacific sea surface temperature (SST) as training data, the method is shown to successfully predict the Niño 3.4 index in a 1998-2017 verification period out to a 10-month lead, which corresponds to an increase of 3-8 months (depending on the decade) over a benchmark linear inverse model (LIM), while significantly improving upon the ENSO predictability "spring barrier". In particular, KAF successfully predicts the historic 2015/16 El Niño at initialization times as early as June 2015, which is comparable to the skill of current dynamical models. An analysis of a 1300-yr control integration of a comprehensive climate model (CCSM4) further demonstrates that the enhanced predictability afforded by KAF holds over potentially much longer leads, extending to 24 months versus 18 months in the benchmark LIM. Probabilistic forecasts for the occurrence of El Niño/La Niña events are also performed and assessed via information-theoretic metrics, showing an improvement of skill over LIM approaches, thus opening an avenue for environmental risk assessment relevant in a variety of contexts.


Location of the cross-β structure in prion fibrils: A search by seeding and electron spin resonance spectroscopy.
Prion diseases are transmissible fatal neurodegenerative disorders spreading between humans and other mammals. The pathogenic agent, prion, is a protease-resistant, β-sheet-rich protein aggregate, converted from a membrane protein called PrPC . PrPSc is the misfolded form of PrPC and undergoes self-propagation to form the infectious amyloids. Since the key hallmark of prion disease is amyloid formation, identifying and studying which segments are involved in the amyloid core can provide molecular details about prion diseases. It has been known that the prion protein could also form non-infectious fibrils in the presence of denaturants. In this study, we employed a combination of site-directed nitroxide spin-labeling, fibril seeding, and electron spin resonance (ESR) spectroscopy to identify the structure of the in vitro-prepared full-length mouse prion fibrils. It is shown that in the in vitro amyloidogenesis, the formation of the amyloid core is linked to an α-to-β structural transformation involving the segment 160-224, which contains strand 2, helix 2, and helix 3. This method is particularly suitable for examining the hetero-seeded amyloid fibril structure, as the unlabeled seeds are invisible by ESR spectroscopy. It can be applied to study the structures of different strains of infectious prions or other amyloid fibrils in the future.


An early-onset retinal dystrophy with dominant inheritance in the Abyssinian cat. Clinical and pathological findings.
The clinical and pathological features of an early-onset autosomal dominant photoreceptor degeneration in the Abyssinian cat are described. Ophthalmoscopic evidence of retinal disease at 8-12 weeks of age was always preceded by marked dilatation of the pupils, impairment of the pupillary light reflex, and nystagmus. The electroretinogram was unrecordable in all but one of the affected individuals examined. Abnormal photoreceptor development was observed by both light and electron microscopy in retinas of a 22-day-old kitten; in this individual, no outer segment material was detected, and inner segments showed impaired development which was more severe towards the posterior pole. In a 40-day-old kitten, the inner segments were relatively well-formed, whereas the outer segments, though present, showed marked disorganization and degenerative change. The retinas of older individuals showed more advanced photoreceptor degeneration, with thinning of the neural retina. This early-onset retinopathy, which may be classified as a rod-cone dysplasia, is distinct from the hereditary retinal dystrophy (progressive retinal atrophy) previously described in this breed. The gene symbol Rdy has been adopted.


Network Pharmacology-Based Approach to Revealing Biological Mechanisms of Qingkailing Injection against IschemicStroke: Focusing on Blood-Brain Barrier.
Ischemic stroke is the most common type of cerebrovascular accident worldwide. It causes long-term disability and death. Qingkailing (QKL) injection is a traditional Chinese patent medicine which has been clinically applied in the treatment of ischemic stroke for nearly thirty years. In the present study, network pharmacology combined with experimentation was used to elucidate the mechanisms of QKL. ADME screening and target prediction identified 62 active compounds and 275 targets for QKL. Topological screening of the protein-protein interaction (PPI) network was used to build a core PPI network consisting of 408 nodes and 17,830 edges. KEGG enrichment indicated that the main signaling pathway implicated in ischemic stroke involved hypoxia-inducible factor-1 (HIF-1). Experimentation showed that QKL alleviated neurological deficits, brain infraction, blood-brain barrier (BBB) leakage, and tight junction degeneration in a mouse ischemic stroke model. Two-photon laser scanning microscopy was used to evaluate BBB permeability and cerebral microvessel structure in living mice. HIF-1α, matrix metalloproteinase-9 (MMP-9), and tight junction proteins such as occludin, zonula occludins-1 (ZO-1), claudin-5, and VE-Cadherin were measured by western blotting. QKL upregulated ZO-1 and downregulated HIF-1α and MMP-9. QKL has a multiapproach, multitarget, and synergistic effect against ischemic stroke.


Development of a modified hollow fibre assay for studying agents targeting the tumour neovasculature.
Previous studies have shown extensive vascularisation surrounding subcutaneously implanted fibres when the duration of the US National Cancer Institute (NCI) hollow fibre assay was prolonged. The feasibility of adapting the NCI assay for evaluating agents targeting the tumour vasculature was investigated in vitro and in vivo. Finally, in the optimised assay, changes in neovasculature formation around the fibres following treatment with the anti-vascular agent paclitaxel were quantified by immunohistochemistry. Correlations between cell number seeded, time in culture and vascular endothelial growth factor (VEGF) secretion were seen. In vivo studies showed that transplanting single rather than 3 fibres at a site reduced inflammation, reducing the length of the fibre transplanted, as did without any significant loss in cell growth over 21 days. A statistically significant reduction in neovascularisation surrounding the fibres was seen accompanying paclitaxel treatment. Modifications made here to the NCI hollow fibre assay demonstrate its potential for analysing anti-tumour vasculature agents.


Antimicrobial susceptibility of Neisseria gonorrhoeae isolated from maternal and child infections in Harare. The Puerperal Sepsis Study Group.
The in vitro antimicrobial susceptibilities of 29 PPNG and 26 non-PPNG isolated from women and neonates in Zimbabwe were investigated. There was evidence of chromosomal resistance to penicillin in many of the non-PPNG strains, with over 60 percent of all isolates having an MIC greater than 1 mg/litre. Reduced susceptibility to tetracycline was evident in about 20 percent of PPNG strains, particularly those containing the 4.4Md plasmid, while over 10 percent of non-PPNGs showed partial resistance to cefuroxime. Less than half of the strains were susceptible to erythromycin (MIC50 greater than 0.5 mg/litre) while all were susceptible to kanamycin and spectinomycin. PPNG containing the 3.2 Md plasmid were very susceptible to thiamphenicol (MIC50 0.25 mg/litre), while other strains were only moderately susceptible (MIC50 2 mg/litre). These findings suggest that penicillin, tetracycline or erythromycin may no longer be relied on for the successful treatment of gonococcal infection in women and babies. Thiamphenicol, Blactamase stable cephalosporins, kanamycin or spectinomycin may be useful alternatives, effective against most strains of both PPNG and non-PPNG. Continued surveillance is recommended to monitor changes in this susceptibility pattern.


Rechallenge of camrelizumab in non-small-cell lung cancer patients treated previously with camrelizumab and microwave ablation.
Camrelizumab is a programmed death receptor-1 inhibitor originally developed in China for the treatment of refractory lymphoma. It has also been effective in non-small-cell lung cancer patients. However, the rechallenge of camrelizumab was not reported previously. We report the rechallenge of camrelizumab therapy in two patients previously treated with microwave ablation (MWA) and camrelizumab. Although objective responses were achieved, camrelizumab therapy was discontinued because of the development of immune-related pneumonia (IRP). Treatment with camrelizumab was reinitiated after the patients recovered from IRP. The reoccurrence of more severe IRP necessitated additional corticosteroid therapy. The rechallenge of camrelizumab in patients treated with MWA plus camrelizumab regimen and who developed IRP should be cautious.


Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.
The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.


Global evidence of expressed sentiment alterations during the COVID-19 pandemic.
The COVID-19 pandemic has created unprecedented burdens on people's physical health and subjective well-being. While countries worldwide have developed platforms to track the evolution of COVID-19 infections and deaths, frequent global measurements of affective states to gauge the emotional impacts of pandemic and related policy interventions remain scarce. Using 654 million geotagged social media posts in over 100 countries, covering 74% of world population, coupled with state-of-the-art natural language processing techniques, we develop a global dataset of expressed sentiment indices to track national- and subnational-level affective states on a daily basis. We present two motivating applications using data from the first wave of COVID-19 (from 1 January to 31 May 2020). First, using regression discontinuity design, we provide consistent evidence that COVID-19 outbreaks caused steep declines in expressed sentiment globally, followed by asymmetric, slower recoveries. Second, applying synthetic control methods, we find moderate to no effects of lockdown policies on expressed sentiment, with large heterogeneity across countries. This study shows how social media data, when coupled with machine learning techniques, can provide real-time measurements of affective states.


Angiomyxoma of the umbilical cord with massive cystic degeneration of Wharton's jelly.
Tumors of the umbilical cord, and especially angiomyxomas, are extremely unusual placental lesions. Sonography three weeks after the finding of a slightly elevated amniotic fluid alpha-fetoprotein, detected a cystic lesion of the umbilical cord in a 35-year-old woman at 19.5 weeks gestation. Two prior sonograms had been normal (16.2 and 17.5 weeks gestational age). After delivery of a normal female infant at 38.5 weeks, a pathologic examination revealed an angiomyxoma of the umbilical cord with massive cystic degeneration of Wharton's jelly. The tumor was twice the size of cases cited previously and cystic degeneration was massive. Serial sonography afforded a unique opportunity to study the development of this lesion in utero.


Motor and sensory nerve transfers in the forearm and hand.
Peripheral nerve injury is a significant problem affecting more than 1 million people around the world each year and poses major challenges to the plastic and reconstructive surgeon. For high upper extremity nerve injuries, distal muscle reinnervation and functional outcomes are generally poor. Tendon transfer has been the traditional reconstructive option in these cases to restore hand function. More recently, nerve transfers have been described in the forearm and hand to recover hand and wrist function and critical sensation. This article reviews the surgical principles, donor nerve options, indications, and outcomes of distal nerve transfers for high upper extremity nerve injuries. The functional results of nerve transfers to date have been comparable to tendon transfers. The primary advantage is the potential for individual finger motion from a donor nerve with singular function. The disadvantage is the longer recovery time required for muscle reinnervation. Nerve transfers are a viable option for peripheral nerve injuries distal to the brachial plexus. The choice of management will depend on the patient's individual goals and priorities in terms of the need or desire for individual finger movement and the length of the recovery period.


[Calculation of the dose of low-intensity laser radiation: the need or the harm?].
This study showed that it is highly undesirable to equip the devices for laser therapy with the dose-calculation function. In order to avoid mistakes, the operator should perform a strict sequence of actions as follows: to choose the needed wavelength and operating regime (the laser head block) of the LILR source, to set and measure the radiation power, the time and frequency of treatment, turn on the apparatus, control its operation and switch it off at the scheduled time. Meeting all these requirements eventually ensures obtaining a certain optimal dose density and guarantees that the entire procedure of laser irradiation is performed in a proper way. The equipment of the apparatus with the dose-calculation function is nothing more than a marketing ploy intended to earn extra money that apart from everything else creates additional problems for the customer.


Use of cariprazine in psychiatric disorders: A systematic review.
Cariprazine was approved for treating schizophrenia and bipolar disorder, and currently is being evaluated for treating depression in clinical trials in the United States. We systematically reviewed the literature on the efficacy and safety of cariprazine. We performed a literature search of the PubMed, MEDLINE, PsycINFO, EMBASE, and Cochrane collaboration databases through August 31, 2016. The search was not restricted by patient age. Articles published in English or official English translations were included. Eleven articles that evaluated the use of cariprazine in the treatment of psychiatric disorders were identified. Four trials evaluated the safety and efficacy of cariprazine in bipolar disorder. One trial investigated its use as an adjunct to antidepressants in major depressive disorder. Three trials evaluated its use in the treatment of acute exacerbations of schizophrenia. Two studies used risperidone or aripiprazole as comparators. Both low- and high-dose cariprazine were more effective than placebo in the treatment of acute mania, mixed episodes, and acute psychosis. Additionally, cariprazine showed efficacy as an adjunctive treatment for depression. Our review indicates that cariprazine demonstrates superior efficacy and good tolerability, both at low and high doses, in the treatment of individuals with psychosis, mania, and depression.


Bacterial Concentration Fluorescence Immunoassay (BCFIA) for the Detection of Periodontopathogens in Plaque.
A bacterial concentration fluorescence immunoassay (BCFIA) was developed to rapidly detect periodontopathic bacteria in human plaque samples. The BCFIA utilized fluorescent-tagged monoclonal antibodies (MAbs) directed against the lipopolysaccharide of selected Gram-negative bacteria. Microorganisms identified in plaque using the BCFIA included Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum. The immunoassay procedure involved combining a patient's plaque sample with a species-specific fluorescein isothiocyanate-labeled MAb and then incubating the mixture in a specialized microtiter plate allowing the MAb to bind to its homologous bacteria. Bound and unbound fluorescent-tagged MAbs were separated by filtration and total bound bacterial fluorescence was determined with a fluorimeter. The relative number of a bacterial species in a given plaque sample was estimated by reference to a standard curve carried through the BCFIA. The BCFIA had a lower detection limit of near 104 specific bacterial cells in a mixed bacterial preparation or plaque sample. When compared to cultivable flora procedures in detecting the 4 periodontopathogens, the BCFIA had high levels of statistical sensitivity, 97% to 100%, while statistical specificity ranged between 57% and 92%. There was a 71% to 82% agreement between BCFIA and DNA probe methodology in detecting periodontopathogens in plaque. The BCFIA, when compared to cultivable flora, offers the advantage of evaluating both live and dead bacterial cells in plaque. This may in part, if not fully, explain the lower specificity values of the BCFIA when compared to cultivable flora. Screening plaque samples for periodontopathic bacteria is considerably faster and results in a greater frequency of detection with BCFIA than cultivable flora based methods. J Periodontol 1992; 63:1093-1101.


Preparative isoelectric focusing of immunologically reactive components of Aspergillus fumigatus mycelium.
A water-soluble mycelial extract of Aspergillus fumigatus has been fractionated by preparative isoelectric focusing using carrier ampholytes in a layer of granulated gel. The separated components were located by staining paper prints from the gel. Within a narrow pH range of 2.5 units, multiple protein bands were visualized with Coomassie Brilliant Blue G. Periodate-Schiff-positive material was generally associated with the major protein zones. When these fractions were eluted the total recovery, calculated on the basis of protein and carbohydrate analyses of the isolated fractions, varied between 20 and 60% of the applied material. Low recoveries were associated with low recoveries of protein; recoveries of carbohydrate were higher and less variable. The immunological activity and specificity of the eluted fractions were assessed in an enzyme-linked immunosorbent assay for the detection of IgG antibodies to A. fumigatus.


Muscle-Skeletal Abnormalities and Muscle Oxygenation during Isokinetic Strength Exercise in Heart Failure with Preserved Ejection Fraction Phenotype: A Cross-Sectional Study.
Exercise intolerance, a hallmark of patients with heart failure (HF), is associated with muscle weakness. However, its causative microcirculatory and muscle characteristics among those with preserved or reduced ejection fraction (HFpEF or HFrEF) phenotype is unclear. The musculoskeletal abnormalities that could result in impaired peripheral microcirculation are sarcopenia and muscle strength reduction in HF, implying lowered oxidative capacity and perfusion affect transport and oxygen utilization during exercise, an essential task from the microvascular muscle function. Besides that, skeletal muscle microcirculatory abnormalities have also been associated with exercise intolerance in HF patients who also present skeletal muscle myopathy. This cross-sectional study aimed to compare the muscle microcirculation dynamics via near-infrared spectroscopy (NIRS) response during an isokinetic muscle strength test and ultrasound-derived parameters (echo intensity was rectus femoris muscle, while the muscle thickness parameter was measured on rectus femoris and quadriceps femoris) in heart failure patients with HFpEF and HFrEF phenotypes and different functional severities (Weber Class A, B, and C). Twenty-eight aged-matched patients with HFpEF (n = 16) and HFrEF (n = 12) were assessed. We found phenotype differences among those with Weber C severity, with HFrEF patients reaching lower oxyhemoglobin (O2Hb, μM) (-10.9 ± 3.8 vs. -23.7 ± 5.7, p = 0.029) during exercise, while HFpEF reached lower O2Hb during the recovery period (-3.0 ± 3.4 vs. 5.9 ± 2.8, p = 0.007). HFpEF with Weber Class C also presented a higher echo intensity than HFrEF patients (29.7 ± 8.4 vs. 15.1 ± 6.8, p = 0.017) among the ultrasound-derived variables. Our preliminary study revealed more pronounced impairments in local microcirculatory dynamics in HFpEF vs. HFrEF patients during a muscle strength exercise, combined with muscle-skeletal abnormalities detected via ultrasound imaging, which may help explain the commonly observed exercise intolerance in HFpEF patients.


L-cysteine as a regulator for arsenic-mediated cancer-promoting and anti-cancer effects.
Previous studies have shown that activities of tyrosine kinases and secretion of the active form of matrix metalloproteinase-2 (MMP-2) are correlated with promotion of tumor growth, while apoptotic cell death in cancer cells is correlated with anti-cancer effects. Although arsenic has been reported to have both cancer-promoting and anti-cancer effects, the mechanisms of the arsenic-mediated bidirectional effects remain unknown. We examined the effects of arsenic on both proto-oncogene c-RET-transfected NIH3T3 cells with benign characters and oncogenic RET-MEN2A-transfected NIH3T3 cells with malignant characters. Arsenic promoted not only c-RET tyrosine kinase activity but also genetically activated RET-MEN2A kinase activity with promotion of dimer formation of RET proteins. Arsenic also increased secretion of the active form of MMP-2 in both RET-MEN2A-transfectants and c-RET-transfectants. On the other hand, arsenic promoted poly-(ADP-ribose) polymerase (PARP) degradation and cell death in both malignant and non-malignant cells. Interestingly, l-cysteine inhibited the arsenic-mediated tumor-promoting effects (activation of kinases and MMP-2 secretion) but not arsenic-mediated anti-cancer effects (PARP degradation and cell death). Our results suggest redox-linked regulation of arsenic-mediated activities of kinases and MMP-2 secretion but not arsenic-mediated cell death. Our results also suggest that l-cysteine is an ideal supplement that inhibits arsenic-mediated tumor-promoting effects without affecting arsenic-mediated anti-cancer effects.


Infestation of Broad Bean (Vicia faba) by the Green Stink Bug (Nezara viridula) Decreases Shoot Abscisic Acid Contents under Well-Watered and Drought Conditions.
The response of broad bean (Vicia faba) plants to water stress alone and in combination with green stink bug (Nezara viridula) infestation was investigated through measurement of: (1) leaf gas exchange; (2) plant hormone titres of abscisic acid (ABA) and its metabolites, and of salicylic acid (SA); and (3) hydrogen peroxide (H2O2) content. Furthermore, we evaluated the effects of experimentally water-stressed broad-bean plants on N. viridula performance in terms of adult host-plant preference, and nymph growth and survival. Water stress significantly reduced both photosynthesis (A) and stomatal conductance (gs ), while infestation by the green stink bug had no effects on photosynthesis but significantly altered partitioning of ABA between roots and shoots. Leaf ABA was decreased and root ABA increased as a result of herbivore attack, under both well-watered and water-deprived conditions. Water stress significantly impacted on SA content in leaves, but not on H2O2. However, infestation of N. viridula greatly increased both SA and H2O2 contents in leaves and roots, which suggests that endogenous SA and H2O2 have roles in plant responses to herbivore infestation. No significant differences were seen for green stink bug choice between well-watered and water-stressed plants. However, for green stink bug nymphs, plant water stress promoted significantly lower weight increases and significantly higher mortality, which indicates that highly water-stressed host plants are less suitable for N. viridula infestation. In conclusion two important findings emerged: (i) association of water stress with herbivore infestation largely changes plant response in terms of phytohormone contents; but (ii) water stress does not affect the preference of the infesting insects, although their performance was impaired.


Detection of myocardial perfusion defects by contrast echocardiography in the setting of acute myocardial ischemia with residual antegrade flow.
Although myocardial contrast echocardiography accurately demarcates area at risk during total coronary occlusion, the ability of MCE to delineate area at risk in the presence of residual antegrade flow is unknown. We hypothesized that perfusion defects in myocardial segments supplied by severe coronary stenoses with residual antegrade flow could be detected by MCE using intravenous FS069. We studied 13 open-chest dogs using an intravenous injection of FS069 during intermittent harmonic imaging. Images were collected at baseline, during acute ischemia with residual antegrade flow, physiologic hyperemia (release of stenosis), and total coronary occlusion. Regional myocardial blood flow was assessed using colored microspheres. MCE risk area during acute ischemia with residual antegrade flow and total occlusion was planimetered and compared with pathologic risk area (area unstained by monastral blue). Background-subtracted peak videointensity in the risk area was assessed for all flow states. Regional myocardial blood flow confirmed expected flow states, being significantly greater during physiologic hyperemia (4.16 +/- 1.22 ml/min/g) than at baseline (0.71 +/- 0.19 ml/min/g) and significantly diminished during coronary stenosis with residual antegrade flow (0.20 +/- 0.16 ml/min/g) and total occlusion (0.09 +/- 0.06 ml/min/g; p < 0.0001). Myocardial risk area by MCE during coronary stenosis with residual antegrade flow correlated well with pathologic risk area determined by monastral blue staining (r = 0.86). Peak videointensity during coronary stenosis (111 +/- 27) was significantly less than at baseline (157 +/- 50) but greater than during total occlusion (81 +/- 34; p < 0.0001). In conclusion, intravenous FS069 in conjunction with intermittent harmonic imaging delineates area at risk in ischemic myocardium supplied by a coronary stenoses with residual antegrade flow. The presence of a perfusion defect on MCE does not necessarily imply that the coronary artery is totally occluded.


Child-oriented word associations improve models of early word learning.
How words are associated within the linguistic environment conveys semantic content; however, different contexts induce different linguistic patterns. For instance, it is well known that adults speak differently to children than to other adults. We present results from a new word association study in which adult participants were instructed to produce either unconstrained or child-oriented responses to each cue, where cues included 672 nouns, verbs, adjectives, and other word forms from the McArthur-Bates Communicative Development Inventory (CDI; Fenson et al., 2006). Child-oriented responses consisted of higher frequency words with fewer letters, earlier ages of acquisition, and higher contextual diversity. Furthermore, the correlations among the responses generated for each pair of cues differed between unconstrained (adult-oriented) and child-oriented responses, suggesting that child-oriented associations imply different semantic structure. A comparison of growth models guided by a semantic network structure revealed that child-oriented associations are more predictive of early lexical growth. Additionally, relative to a growth model based on a corpus of naturalistic child-directed speech, the child-oriented associations explain added unique variance to lexical growth. Thus, these new child-oriented word association norms provide novel insight into the semantic context of young children and early lexical development.


Advances in Fungal Peptide Vaccines.
Vaccination is one of the greatest public health achievements in the past century, protecting and improving the quality of life of the population worldwide. However, a safe and effective vaccine for therapeutic or prophylactic treatment of fungal infections is not yet available. The lack of a vaccine for fungi is a problem of increasing importance as the incidence of diverse species, including Paracoccidioides, Aspergillus, Candida, Sporothrix, and Coccidioides, has increased in recent decades and new drug-resistant pathogenic fungi are emerging. In fact, our antifungal armamentarium too frequently fails to effectively control or cure mycoses, leading to high rates of mortality and morbidity. With this in mind, many groups are working towards identifying effective and safe vaccines for fungal pathogens, with a particular focus of generating vaccines that will work in individuals with compromised immunity who bear the major burden of infections from these microbes. In this review, we detail advances in the development of vaccines for pathogenic fungi, and highlight new methodologies using immunoproteomic techniques and bioinformatic tools that have led to new vaccine formulations, like peptide-based vaccines.


Transformation and motility of human platelets: details of the shape change and release reaction observed by optical and electron microscopy.
Blood platelets from 10 normal human subjects have been examined with a sensitive differential interference contrast (DIC) microscope. The entire transformation process during adhesion to glass is clearly visible and has been recorded cinematographically, including the disk to sphere change of shape, the formation of sessile protuberances, the extension and retraction of pseudopodia, and the spreading, ruffling, and occasional regression of the hyalomere. The exocytosis of intact dense bodies can be observed either by DIC microscopy, or by epifluorescence microscopy in platelets stained with mepacrine. Details of fluorescent flashes indicate that the dense bodies usually release their contents extracellularly, may do so intracytoplasmically under the influence of strong, short wavelength light on some preparations of mepacrine-stained platelets. The release of one or more dense bodies leaves a crater of variable size on the upper surface of the granulomere. Such craters represent the surface component of the open canalicular system and their formation and disappearance can be directly observed. Because these techniques permit quantitation of several parameters of motility which are not readily observable by other techniques, it is suggested that high extinction DIC microscope examination may become a rapid and useful method of studying congenital and acquired platelet disorders. Many features of platelet transformation have been confirmed and extended by scanning electron micrographs. These can in turn be interpreted by reference to time-lapse films of living platelets.


Role of food allergy in asthma in childhood.
Atopy is the major predisposing factor for asthma identified up to now, and allergen exposure, particularly indoor allergens, is considered as a causal factor for asthma. Food allergy is frequently underestimated in association with asthma, however food allergy has been shown to trigger or exacerbate broncho-obstruction in 2 to 8.5% of children with asthma. There is also evidence that double-blind placebo-controlled oral challenge is able to increase unspecific bronchial hyperresponsiveness. Sensitization to food can occur early in life involving T cell response, mainly of the Th2 phenotype, but also IgE-mediated hypersensitivity. Moreover, it has been shown that sensitization to food allergens early in life is a risk factor for sensitization to inhalent allergens and respiratory symptoms later on. Epidemiological studies suggest that changes in the dietary composition, such as trans-fatty acids, could be involved in the increase of asthma prevalence. The introduction of formula during the first trimester of life increases the risk of having asthma. The diagnosis of food allergy associated with asthma is not easy, nevertheless is important for allergists, pulmonologists and paediatricians to consider food allergy in children with respiratory symptoms, especially when asthma symptoms start early in life and when they are associated with other manifestations of food allergy. Children sensitized to cow's milk proteins and also having atopic eczema are at higher risk for asthma. Since avoidance of the offending food is the first step in the management of children with asthma associated with food allergy, a careful identification should be done in order to avoid unnecessary elimination of foods.


Cancer stem cells and brain tumors.
Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors.


Halomonas titanicae sp. nov., a halophilic bacterium isolated from the RMS Titanic.
A Gram-negative, heterotrophic, aerobic, non-endospore-forming, peritrichously flagellated and motile bacterial strain, designated BH1(T), was isolated from samples of rusticles, which are formed in part by a consortium of micro-organisms, collected from the RMS Titanic wreck site. The strain grew optimally at 30-37°C, pH 7.0-7.5 and in the presence of 2-8 % (w/v) NaCl. We carried out a polyphasic taxonomic study in order to characterize the strain in detail. Phylogenetic analyses based on 16S rRNA gene sequence comparison indicated that strain BH1(T) clustered within the branch consisting of species of Halomonas. The most closely related type strains were Halomonas neptunia (98.6 % 16S rRNA sequence similarity), Halomonas variabilis (98.4 %), Halomonas boliviensis (98.3 %) and Halomonas sulfidaeris (97.5 %). Other closely related species were Halomonas alkaliphila (96.5 % sequence similarity), Halomonas hydrothermalis (96.3 %), Halomonas gomseomensis (96.3 %), Halomonas venusta (96.3 %) and Halomonas meridiana (96.2 %). The major fatty acids of strain BH1(T) were C(18 : 1)ω7c (36.3 %), C(16 : 0) (18.4 %) and C(19 : 0) cyclo ω8c (17.9 %). The DNA G+C content was 60.0 mol% (T(m)). Ubiquinone 9 (Q-9) was the major lipoquinone. The phenotypic features, fatty acid profile and DNA G+C content further supported the placement of strain BH1(T) in the genus Halomonas. DNA-DNA hybridization values between strain BH1(T) and H. neptunia CECT 5815(T), H. variabilis DSM 3051(T), H. boliviensis DSM 15516(T) and H. sulfidaeris CECT 5817(T) were 19, 17, 30 and 29 %, respectively, supporting the differential taxonomic status of BH1(T). On the basis of the phenotypic, chemotaxonomic and phylogenetic data, strain BH1(T) is considered to represent a novel species, for which the name Halomonas titanicae sp. nov. is proposed. The type strain is BH1(T) (=ATCC BAA-1257(T) =CECT 7585(T) =JCM 16411(T) =LMG 25388(T)).


The current role and future prospects of paclitaxel in the treatment of small cell lung cancer.
When combination regimens containing a platinum compound and etoposide are used, median survivals in patients with extensive- and limited-stage small cell lung cancer are 7 to 10 months and 15 to 20 months, respectively. A recent randomized trial demonstrated equivalent efficacy and decreased toxicity with carboplatin/etoposide compared with cisplatin/etoposide. Because of excellent single-agent activity, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been recently added to various platinum/etoposide combinations. Phase I/II studies with paclitaxel/cisplatin/etoposide and paclitaxel/carboplatin/etoposide have demonstrated excellent activity with acceptable toxicity. Ongoing phase III trials will better define the contribution of paclitaxel to standard platinum/etoposide regimens. In addition, phase II trials of novel paclitaxel combinations (e.g., paclitaxel/topotecan, paclitaxel/carboplatin/topotecan) are ongoing.


Towards sustainable healthcare system performance in the 21st century in high-income countries: a protocol for a systematic review of the grey literature.
There is wide recognition that, if healthcare systems continue along current trajectories, they will become harder to sustain. Ageing populations, accelerating rates of chronic disease, increasing costs, inefficiencies, wasteful spending and low-value care pose significant challenges to healthcare system durability. Sustainable healthcare systems are important to patients, society, policy-makers, public and private funders, the healthcare workforce and researchers. To capture current thinking about improving healthcare system sustainability, we present a protocol for the systematic review of grey literature to capture the current state-of-knowledge and to compliment a review of peer-reviewed literature. The proposed search strategy, based on the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, includes Google Advanced Search, snowballing techniques and targeted hand searching of websites of lead organisations such as WHO, Organisation for Economic Cooperation and Development, governments, public policy institutes, universities and non-government organisations. Documents will be selected after reviewing document summaries. Included documents will undergo full-text review. The following criteria will be used: grey literature document; English language; published January 2013-March 2018; relevant to the healthcare delivery system; the content has international or national scope in high-income countries. Documents will be assessed for quality, credibility and objectivity using validated checklists. Descriptive data elements will be extracted: identified sustainability threats, definitions of sustainability, attributes of sustainable healthcare systems, solutions for improvement and outcome measures of sustainability. Data will be analysed using novel text-mining methods to identify common concept themes and meanings. This will be triangulated with the more traditional analysis and concept theming by the researchers. No primary data will be collected, therefore ethical approval will not be sought. The results will be disseminated in peer-reviewed literature, as conference presentations and as condensed summaries for policy-makers and health system partners. CRD42018103076.


Prognostic value of pretreatment serum beta-2 microglobulin level in advanced classical Hodgkin lymphoma treated in the modern era.
The prognostic value of pretreatment serum beta-2 microglobulin (B2MG) level in advanced Hodgkin lymphoma (HL) patients treated in the modern era has not been well established. We conducted a retrospective study involving 202 advanced classical HL (cHL) patients treated from 1998.5 to 2015.7 to evaluate the impact of serum B2MG level on prognosis. Multivariate analysis showed that serum B2MG level ≥ 2.5 mg/L was an independent predictor for freedom from progression (FFP) (P = 0.001), lymphoma-specific survival (P = 0.030) and overall survival (P = 0.034). The 5-year FFP of patients with serum B2MG level ≥ 2.5 mg/L was 66.8%, compared with 89.7% in patients with B2MG level < 2.5 mg/L (P < 0.001). The traditionally used International Prognostic Score (IPS) remained prognostic for FFP (P = 0.013) but the predictive range narrowed, with 5-year FFP ranging from 90.9% to 62.3%. The 5-year FFP of the 44 patients with both IPS ≥ 3 and serum B2MG ≥ 2.5 mg/L was 50.7%, which was significantly worse than that of the 87 patients with only one of the two factors (81.9%, P < 0.001) or the 71 patients with both B2MG < 2.5 mg/L and IPS < 3 (91.1%, P < 0.001). The difference of FFP between the latter two groups was smaller but also significant (P = 0.038). In summary, our data suggest pretreatment serum B2MG level ≥ 2.5 mg/L was an independent unfavorable prognostic factor in advanced cHL patients treated in the modern era. It improves IPS in predicting the outcomes as the combination of IPS and B2MG indentified a wider prognostic range than IPS alone with a sizable number of patients in different risk groups.


Antibiotic Prophylaxis Protocols and Surgical Site Infection Rates in Trauma Surgery: A Prospective Regional Study of 26,849 Procedures.
Prophylactic antibiotics have been shown to reduce the rate of surgical site infection (SSI) 1, however there is little evidence supporting the effectiveness of one antibiotic over another. We have studied SSI rates and antibiotic prophylaxis protocols in Northern Ireland trauma surgery over a 10-year period to Identify the most effective antibiotic protocol associated with lowest rate of SSI. Antibiotic prophylaxis protocols from 2004-2014 were sought from each of the region's 4 trauma hospitals and their dates of introduction recorded. For the same period, the number of trauma procedures carried out quarterly and the number of SSIs were recorded for each hospital from the return of prospectively collected SSI surveillance forms. 26849 trauma procedures were included with an overall SSI rate of 1.34% (95% Confidence interval [CI] 1.21 to 1.49). Single dose flucloxacillin (2 grams) with single dose gentamicin (3mg/kg) was the most commonly used protocol used in 3 different hospitals for a combined 13.5 years covering 11445 procedures. The SSI rate was 0.72% (95% CI 0.58-0.89). Triple dose cefuroxime (1.5 grams) was used in 2 different hospitals for a combined 10 years covering 8864 procedures. The SSI rate for this regime was 2.46% (95% CI 2.16-2.80). Single dose cefuroxime (1.5 grams) was used in 2 different hospitals for a combined 8 years covering 6540 procedures. The SSI rate was 0.92% (95% CI 0.71-1.18). In this prospective observational cohort study prophylaxis using flucloxacillin and gentamicin was associated with the lowest SSI rate. Single dose cefuroxime was associated with a lower rate of SSI compared to triple dose (p<0.001). Identification of antibiotic regimes associated with the lowest SSI rates will promote the judicious use of antibiotics, improve antibiotic stewardship while allowing for continued benefit in the prevention of SSI in an era of ever-increasing antibiotic resistance.


Long-term behavior of secretory immunity in ileocecal and ileal orthotopic neobladders.
To compare secretory immunity in cecal and ileal orthotopic neobladders, and to detect its permanence over time. IgA was studied in the urine of 33 patients with ileocecourethrostomy (ICUS) and 13 patients with ileal reservoir (IR). The mean follow-up was 55 months. Results were compared in terms of the type of operation, a healthy control group, and the time since surgery. Urinary IgA levels were significantly higher in ICUS and IR patients than in normal controls. No significant differences in IgA concentrations were detected in patients with different reservoirs and with regard to time. Both the reservoirs maintain the function of producing IgA. In particular no differences were detected over time and urine could be a permanent antigenic stimulus. IgA could be considered an adjunctive factor for upper urinary tract protection. For this reason we prefer to use a simple, indirect antireflux mechanism, thus avoiding direct manipulation of the uretero-intestinal anastomosis.


HIV-1 subtype B protease and reverse transcriptase amino acid covariation.
Despite the high degree of HIV-1 protease and reverse transcriptase (RT) mutation in the setting of antiretroviral therapy, the spectrum of possible virus variants appears to be limited by patterns of amino acid covariation. We analyzed patterns of amino acid covariation in protease and RT sequences from more than 7,000 persons infected with HIV-1 subtype B viruses obtained from the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu). In addition, we examined the relationship between conditional probabilities associated with a pair of mutations and the order in which those mutations developed in viruses for which longitudinal sequence data were available. Patterns of RT covariation were dominated by the distinct clustering of Type I and Type II thymidine analog mutations and the Q151M-associated mutations. Patterns of protease covariation were dominated by the clustering of nelfinavir-associated mutations (D30N and N88D), two main groups of protease inhibitor (PI)-resistance mutations associated either with V82A or L90M, and a tight cluster of mutations associated with decreased susceptibility to amprenavir and the most recently approved PI darunavir. Different patterns of covariation were frequently observed for different mutations at the same position including the RT mutations T69D versus T69N, L74V versus L74I, V75I versus V75M, T215F versus T215Y, and K219Q/E versus K219N/R, and the protease mutations M46I versus M46L, I54V versus I54M/L, and N88D versus N88S. Sequence data from persons with correlated mutations in whom earlier sequences were available confirmed that the conditional probabilities associated with correlated mutation pairs could be used to predict the order in which the mutations were likely to have developed. Whereas accessory nucleoside RT inhibitor-resistance mutations nearly always follow primary nucleoside RT inhibitor-resistance mutations, accessory PI-resistance mutations often preceded primary PI-resistance mutations.


Development of the rat sublingual gland: a light and electron microscopic immunocytochemical study.
Cell differentiation in the rat sublingual gland occurs rapidly and is largely complete by birth. To study differentiation of the serous and mucous cells of the sublingual gland, we used antibodies to the secretory proteins CSP-1, SMGB, PSP, and SMGD, and sublingual mucin as specific cell markers. Glands from rats at ages 18, 19, and 20 days in utero, and postnatal days 0, 1, 5, 9, 14, 18, 25, 40, and 60 were fixed and prepared for morphological analysis and immunocytochemical labeling. At age 18 days in utero, a few cells in the developing terminal bulbs contained mucous-like apical granules that labeled with anti-mucin. Other cells had mixed granules with a peripheral lucent region and a dense core of variable size that occasionally labeled with anti-SMGD. Additionally, presumptive serous cells with small dense granules that contained CSP-1 and SMGB were present. At age 19 days in utero, the dense granules of these cells also labeled with anti-SMGD. By age 20 days in utero, mucous cells were filled with large, pale granules that labeled with anti-mucin, and serous cells had numerous dense granules containing CSP-1, SMGB, PSP, and SMGD. Fewer cells with mixed granules were seen, but dense regions present in some mucous granules (MGs) labeled with anti-SMGD. After birth, fewer MGs had dense regions, and serous cells were organized into well-formed demilunes. Except for PSP, which was undetectable after the fifth postnatal day, the pattern of immunoreactivity observed in glands of neonatal and adult animals was similar to that seen by age 20 days in utero. These results suggest that mucous and serous cells have separate developmental origins, mucous cells differentiate earlier than serous cells, and cells with mixed granules may become mucous cells.


Future continental summer warming constrained by the present-day seasonal cycle of surface hydrology.
Present-day land temperatures simulated by state-of-the-art global climate models exhibit considerable uncertainty. Generally it is assumed that these temperature biases do not affect the projected warming in response to rising greenhouse gas concentrations (i.e. drop out by subtracting projected and present-day temperatures), but for specific regions and seasons this assumption is invalid. Here we show that, on the contrary, for large continental regions, such as Europe, state-of-the art global climate models with a warm summer bias project a relatively strong warming. This is because continental summer temperatures depend chiefly on soil drying in response to spring and summer solar radiation increase: models that dry fastest (due to the interaction of clouds, convection and soil hydrology) exhibit the strongest reductions in evaporation and consequently a more pronounced end-of-summer warming. These physical mechanisms acting on a seasonal timescale also govern the long-term climate response to greenhouse forcing over continental regions in summer. Combining these findings, we use the current model biases to reduce the uncertainty range in the projected warming over Europe from 3.6-8.6 °C to 4.6-7.3 °C (a reduction of about 50%). Given the huge potential impacts of the warmest projections on health, agriculture and water management, constraining the range of future summer climate change is imperative for relevant mitigation and adaptation strategies.


First Report of Peanut mottle virus Infecting Soybean in South Korea.
In July 2013, soybean (Glycine max) plants at the research field in Daegu, South Korea, showed virus-like symptoms, such as mosaic, mottle, yellowing, and stunting. Overall, there were approximately 1% of soybean plants that showed these symptoms. Sixteen soybean samples were collected based on visual symptoms and subjected to laboratory characterization. Total RNA was extracted from each sample with the Tri Reagent (Molecular Research Center, Cincinnati, OH) and cDNA was synthesized using random N25 primer with RevertAid Reverse Transcriptase (Thermo Scientific, Waltham, MA), according to the manufacturers' instructions. All samples were tested by PCR with Prime Taq Premix (2X) (GeNet Bio, Daejeon, Korea) and primer sets specific to Soybean mosaic virus (SMV; 5'-CATATCAGTTTGTTGGGCA-3' and 5'-TGCCTATACCCTCAACAT-3'), Peanut stunt virus (PSV; 5'-TGACCGCGTGCCAGTAGGAT-3' and 5'-AGGTDGCTTTCTWTTGRATTTA-3'), Soybean yellow mottle mosaic virus (SYMMV; 5'-CAACCCTCAGCCACATTCAACTAT-3' and 5'-TCTAACCACCCCACCCGAAGGATT-3'), and Soybean yellow common mosaic virus (SYCMV; 5'-TTGGCTGAGAGGAGTGGCTT-3' and 5'-TGCGGTCGTGTAGTCAGTG-3'). Among 16 samples tested, five were positive for SMV and two for SYMMV. Three samples were found infected by both SMV and SYMMV and four by both SMV and PSV. Since two of the symptomatic samples were not infected by viruses described above, a pair of primers specific to Peanut mottle virus (PeMoV; 5'-GCTGTGAATTGTTGTTGAGAA-3' and 5'-ACAATGATGAAGTTCGTTAC-3') was tested (1). All 16 samples were subjected to RT-PCR with primers specific to PeMoV. Four were found positive for PeMoV. Two of them were already found infected with SYMMV. In order to identify the complete nucleotide sequences of PeMoV coat protein (CP), another primer set (5'-TGAGCAGGAAAGAATTGTTTC-3' and 5'-GGAAGCGATATACACACCAAC-3') was used. RT-PCR product was cloned into RBC TA Cloning Vector (RBC Bioscience, Taipei, Taiwan) and the nucleotide sequence of the insert was determined by Macrogen (Seoul, Korea). CP gene of the PeMoV (GenBank Accession No. KJ664838) showed the highest nucleotide sequence identity with PeMoV isolate Habin (KF977830; 99% identity), and the highest amino acid identity with GenBank Accession No. ABI97347 (100% identity). In order to fulfill Koch's postulates, several G. max cv. Williams 82 were inoculated with the extracts of PeMoV-infected leaf tissue. At 14 days post-inoculation, plants showed systemic mottle symptoms. These symptomatic plants were subjected to RT-PCR, and the nucleotide sequences of the PCR product were found identical to that of the virus in the inoculum. To our knowledge, this is the first report of soybean-infecting PeMoV, a member of the genus Potyvirus in the family Potyviridae, in South Korea. Reference: (1) R. G. Dietzgen et al. Plant Dis. 85:989, 2001.


[Prenatal diagnosis of type II Arnold Chiari malformation].
During a 7-year-period 22 foetuses with an Arnold-Chiari deformity were diagnosed. The reason for referring to our centre were severe additional malformations. In 2 cases protrusion of the fetal brainstem is documented by sonography prenatally. Prenatal diagnosis of an ACM has not been documented in the literature. The cytogenetic and microbiological findings including the additional malformations are presented. Pathogenesis, outcome and treatment options are discussed.


A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes.
Diabetes mellitus and septic shock increase the incidence of mortality by thrombosis. Although kinin B1 receptor (B1R) is involved in both pathologies, its role in platelet function and thrombosis remains unknown. This study investigates the expression, the inflammatory, and pro-thrombotic effects of B1R in a model of septic shock in diabetic rats. Sprague-Dawley rats were made diabetic with streptozotocin (STZ) (65 mg/kg, i.p.). Four days later, control and STZ-diabetic rats were injected with lipopolysaccharide (LPS) (2 mg/kg, i.p.) or the vehicle. B1R antagonist (SSR240612, 10 mg/kg by gavage) was given either acutely (12 and 24 h prior to endpoint analysis) or daily for up to 7 days. Moreover, a 7-day treatment was given either with cyclooxygenase (COX)-2 inhibitor (niflumic acid, 5 mg/kg, i.p.), non-selective COX-1 and COX-2 inhibitor (indomethacin, 10 mg/kg, i.p.), non-selective nitric oxide synthase (NOS) inhibitor (L-NAME, 50 mg/kg by gavage), iNOS inhibitor (1400W, 5 mg/kg, i.p.), or heparin (100 IU/kg, s.c.). The following endpoints were measured: edema and vascular permeability (Evans blue dye), B1R expression (qRT-PCR, western blot, flow cytometry), aggregation in platelet-rich plasma (optical aggregometry), and organ damage (histology). Rats treated with STZ, LPS, and STZ plus LPS showed significant increases in edema and vascular permeability (heart, kidney, lung, and liver) and increased expression of B1R in heart and kidney (mRNA) and platelets (protein). Lethal septic shock induced by LPS was enhanced in STZ-diabetic rats and was associated with lung and kidney damage, including platelet micro-aggregate formation. SSR240612 prevented all these abnormalities as well as STZ-induced hyperglycemia and LPS-induced hyperthermia. Similarly to SSR240612, blockade of iNOS and COX-2 improved survival. Data provide the first evidence that kinin B1R plays a primary role in lethal thrombosis in a rat model of septic shock in diabetes. Pharmacological rescue was made possible with B1R antagonism or by inhibition of iNOS and COX-2, which may act as downstream mechanisms.


Measuring the health status of children with hydrocephalus by using a new outcome measure.
In the preceding article, the authors described the Hydrocephalus Outcome Questionnaire (HOQ), a simple, reliable, and valid measure of health status in children with hydrocephalus. In the present study, they present their initial experience in using the HOQ to quantify the health status in a typical cohort of children with hydrocephalus. The mothers of children with hydrocephalus completed the HOQ and, with the child's attending surgeon, provided a global rating of their children's health. An exploratory analysis was performed using a multivariate analysis of variance (ANOVA) to determine which variables might be associated with worse health status. The mothers of 80 children, ranging in age from 5 to 17 years, participated in the study. The mean HOQ Overall Health score was 0.68, a value estimated to be equivalent to a mean health utility score of 0.77. The global health ratings provided by the mothers and the surgeons were moderately correlated with the HOQ scores (Pearson correlations 0.58 and 0.57, respectively). Results of the multivariate ANOVA indicated that the presence of epilepsy was strongly associated with a worse health status (p < 0.0001, F-test). The health status of a typical sample of children with hydrocephalus was measured using the HOQ. The only consistently significant association with health status found was the presence of epilepsy.


Formation and self-organization kinetics of alpha-CD/PEO-based pseudo-polyrotaxanes in water. A specific behavior at 30 degrees C.
alpha-Cyclodextrins (alpha-CDs) have the ability to form inclusion complexes with poly(ethylene oxide) (PEO) polymer chains. These pseudo-polyrotaxanes (PPRs) can be obtained by quenching an alpha-CD/PEO mixture in water from 70 degrees C down to a lower temperature (typically in the range from 5 to 30 degrees C) thanks to favorable interactions between alpha-CD cavities and PEO chains. Moreover, starting from a liquid alpha-CD/PEO mixture at a total mass fraction of 15% w/w at 70 degrees C, the formation of PPRs with time at a lower temperature induces a white physical gel with time, and phase separation is observed. We established that PPR molecules are exclusively found in the precipitated phase although unthreaded alpha-CD molecules and unthreaded PEO chains are in the liquid phase. At 30 degrees C, the physical gel formation is much slower than at 5 degrees C. At 30 degrees C, we established that, in a first step, alpha-CDs thread onto PEO chains, forming PPR molecules which are not in good solvent conditions in water. At a higher length scale, rapid aggregation of the PPR molecules occurs, and threaded alpha-CD-based nanocylinders form (cylinder length L = 5.7 nm and cylinder radius R = 4.7 nm). At a higher length scale, alpha-CD-based nanocylinders associate in a Gaussian way, engendering the formation of precipitated domains which are responsible for the high turbidity of the studied system. At the end of this first step (i.e., after 20 min), the system still remains liquid and the PPRs are totally formed. Then, in a second step (i.e., after 150 min), the system undergoes its reorganization characterized by a compacity increase of the precipitated domains and forms a physical gel. We found that PPRs are totally formed after 20 min at 30 degrees C and that the system stays in a nongel state up to 150 min. This opens new perspectives regarding the PPR chemical modification: between these two characteristic times, we can easily envisage an efficient chemical modification of the PPR molecules in water, as for instance an end-capping reaction leading to the synthesis of polyrotaxanes.


Larvicidal activity of the leaf extracts of Spondias mombin Linn. (Anacardiaceae) from various solvents against malarial, dengue and filarial vector mosquitoes (Diptera: Culicidae).
Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus are vector mosquitoes of dengue, malaria, and filariasis, respectively. Since no vaccine is available to treat these diseases, the control of the main mosquito vectors is essential. As conventional insecticides have limited success, plants may be alternative larvicidal agents, since they contain a rich source of bioactive chemicals. The aim of this study was to evaluate the larvicidal activity of methanol crude extract, hexane, dichloromethane, acetone, ethyl acetate and methanol fractions of Spondias mombin leaf against IV instar larvae of dengue, malaria, and lymphatic filariasis vector mosquitoes. A total of 25, IV instar larvae of each target mosquito species were exposed to various concentrations (125-1000 ppm) and were assayed in the laboratory by using the protocol of WHO 2005; the LC50 values were determined by Probit analysis. Hexane, dichloromethane and acetone fractions were the most effective against Ae. aegypti with LC50 values of 22.54, 42.13, 45.18 ppm, respectively. Hexane fraction registered the highest activity with LC50 of 92.20 ppm against An. gambiae. It was still hexane fraction that showed better toxicity with LC50 of 326.53 ppm against Cx. quinquefasciatus. The Spondias mombin leaf extracts proved to be a strong candidate for a natural, safe and stable mosquito larvicide to be used in population control of Ae. aegypti, An. gambiae and Cx. quinquefasciatus and so may replace the conventional Diclorvos to control malaria, dengue and filariasis in Nigeria.


Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas.
We aimed to define the dose of pirfenidone in children and adolescents with neurofibromatosis 1 and plexiform neurofibromas that is pharmacokinetically comparable to the active adult dose. Pirfenidone was administered orally on a continuous dosing schedule. The starting dose level was 250 mg/m2/dose. The second dose level (500 mg/m2/dose) corresponded to the adult dose that previously showed activity in sclerosing conditions. A dose was considered pharmacokinetically comparable if the drug exposure in children was <1 standard deviation below the drug exposure in adults treated with 800 mg three times a day. Pharmacokinetic sampling was performed for 24 hours after the first dose. Response to treatment was evaluated using automated volumetric magnetic resonance imaging analysis; quality of life was evaluated using the Impact of Pediatric Illness Scale. Sixteen patients were entered and evaluated for toxicity. Dose-limiting toxicities were observed in 2 of 12 patients receiving 500 mg/m2 three times a day. The plasma pharmacokinetics of pirfenidone were highly variable, but not age dependent. The second dose level was the pharmacokinetically comparable dose and is being used in an ongoing phase II trial of pirfenidone for children with neurofibromatosis 1 and progressive plexiform neurofibroma.


Superficial mucoceles and lichenoid graft versus host disease: report of three cases.
Superficial mucoceles are subepithelial extravasations of sialomucin that occur at the epithelial-connective tissue interface and are directly related to minor salivary glands. They have been described in association with oral lichen planus and, exceptionally, with chronic graft versus host disease. Three patients who underwent an allogeneic bone marrow transplantation for a chronic myelogenous leukaemia presented multiple superficial mucoceles and an oral lichenoid graft versus host disease.


Role of GALNT2 on Insulin Sensitivity, Lipid Metabolism and Fat Homeostasis.
O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society.


[Emergency room deaths.]
3-MONTH RETROSPECTIVE ANALYSIS: OBJECTIVES: Determine the characteristics of patients who died in the emergency unit and assess the number for whom care was limited or withdrawn. METHODS: A 3-month single-center retrospective study of all the patients who died in the emergency room. Bivariate analysis was used to compare the clinical characteristics of patients who died despite maximum care (MC) with those for whom care was limited (LC). RESULTS: 84 patients died during the study period: 48 men and 36 women (mean age: 73 +/- 18 years). Half had normal mobility (43 patients, 50%), and 35 (40%) lived at home. Nearly all (72 patients, 72%) had a severe chronic disease. In descending order, death was ascribed to neurological (n=22, 24%), cardiac (n=14, 15%), septic (n=13, 14%) and respiratory (n=9, 10%) causes. The decision was made to limit or stop active care for 73 patients (84%) and recorded in 48 case files (55%). The principal differences between patients receiving MC and LC were respectively C and D Knaus classification and their age. CONCLUSION: Death is frequent in emergency units and often strikes elderly patients with impaired mobility and severe chronic diseases. The decisions to limit or stop active care are the predominant direct cause, but their modalities warrant further exploration in a prospective study.


Family with sequence similarity 111 member B contributes to tumor growth and metastasis by mediating cell proliferation, invasion, and EMT via transforming acidic coiled-coil protein 3/PI3K/AKT signaling pathway in hepatocellular carcinoma.
As a complex systemic disease, primary liver cancer ranks third in death rate for solid tumors worldwide. Family with sequence similarity 111 member B (FAM111B), which was found to be aberrantly mutated in multiple cancers, is a candidate oncogene. We aimed to determine the function and mechanism of FAM111B in hepatocellular carcinoma (HCC). The expression of FAM111B was evaluated in HCC tissues, adjacent tissues, HCC cell lines. The impact of FAM111B on proliferation, invasion, apoptosis and EMT of HCC cells were detected by CCK-8, Transwell, flow cytometry and Western blot assays. The relationship between FAM111B and transforming acidic coiled-coil protein 3 (TACC3) was assessed by CoIP and Immunofluorescence (IF) staining assays. The effect of FAM111B on tumor growth was detected by using xenograft model of nude mice. The expression of FAM111B was upregulated in HCC tissues and cell lines, and the prognosis of HCC patients was worse in the high FAM111B expression group, and its expression level was associated with the TNM stage of HCC. FAM111B silencing inhibited HCC cell proliferation and invasion, EMT and induced apoptosis. Besides, TACC3 served as an interactor for FAM111B, which could enhance TACC3 expression, thus activing PI3K/AKT pathway. Rescue experiments revealed that elevated of TACC3 restored the inhibitory effect of FAM111B overexpression on the cell functions via PI3K/AKT pathway. In vivo, FAM111B inhibition hampered tumor growth and metastasis of HCC. This study highlighted a key player of FAM111B in modulating the malignant biological progression of HCC via TACC3/PI3K/AKT signaling pathway, displaying a potential therapeutic target for HCC.


Pseudomonas aeruginosa exotoxin Y is a promiscuous cyclase that increases endothelial tau phosphorylation and permeability.
Exotoxin Y (ExoY) is a type III secretion system effector found in ~ 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY causes inter-endothelial gaps and vascular leak, the mechanisms by which this occurs are poorly understood. Using both a bacteria-delivered and a codon-optimized conditionally expressed ExoY, we report that this toxin is a dual soluble adenylyl and guanylyl cyclase that results in intracellular cAMP and cGMP accumulation. The enzymatic activity of ExoY caused phosphorylation of endothelial Tau serine 214, accumulation of insoluble Tau, inter-endothelial cell gap formation, and increased macromolecular permeability. To discern whether the cAMP or cGMP signal was responsible for Tau phosphorylation and barrier disruption, pulmonary microvascular endothelial cells were engineered for the conditional expression of either wild-type guanylyl cyclase, which synthesizes cGMP, or a mutated guanylyl cyclase, which synthesizes cAMP. Sodium nitroprusside stimulation of the cGMP-generating cyclase resulted in transient Tau serine 214 phosphorylation and gap formation, whereas stimulation of the cAMP-generating cyclase induced a robust increase in Tau serine 214 phosphorylation, gap formation, and macromolecular permeability. These results indicate that the cAMP signal is the dominant stimulus for Tau phosphorylation. Hence, ExoY is a promiscuous cyclase and edema factor that uses cAMP and, to some extent, cGMP to induce the hyperphosphorylation and insolubility of endothelial Tau. Because hyperphosphorylated and insoluble Tau are hallmarks in neurodegenerative tauopathies such as Alzheimer disease, acute Pseudomonas infections cause a pathophysiological sequela in endothelium previously recognized only in chronic neurodegenerative diseases.


[The accelerated training of skin-fascia flaps].
The suggested method for training cutaneofascial flaps is based on the results of histological studies, it can be applied in the early postoperative period, and reduces the intervals between the stages of plastic surgery with flaps. Training is possible in any localization of the cutaneofascial flap.


Problems and controversies in the management of hematogenous candidiasis.
Hematogenous candidiasis is associated with substantial mortality and morbidity. Amphotericin B has routinely been used to treat this infection. However, tolerance of therapy with amphotericin B is limited by the drug's toxicity. The results of recently completed prospective randomized clinical studies comparing amphotericin B with fluconazole for the treatment of hematogenous candididiasis suggest that fluconazole is as effective as amphotericin B and that fluconazole is better tolerated by patients. Nevertheless, several questions remain to be answered regarding the optimal choice of antifungal agent for both nonneutropenic and neutropenic patients, the dosing schedule and duration of therapy, the role of combination antifungal therapy, and the efficacy of the lipid formulations of polyenes. Controversial issues with respect to the role of central venous catheters in the pathogenesis of hematogenous candidiasis, as well as the roles of cytokines and white blood cell transfusions in the treatment of neutropenic patients with hematogenous candidiasis, also need to be addressed.


Cardiac problems associated with dysbarism.
Patient salvage rates depend on the extent of injury, speed and appropriateness of treatment, and the patient's age and state of health in addition to other variables. Undertreatment of DII may result in significant morbidity and associated costs. If there is any doubt regarding whether a patient might benefit from treatment, a trial at pressure is indicated. Among those with AGE who reach recompression within 5 minutes, the death rate may be only 5%, and those who survive have little morbidity. Among those whose recompression delay increases to 5 hours, however, mortality approaches 10%, and more than 50% of the survivors experience residua. All dive accidents should be thoroughly investigated by professionals. Sport divers who manifest any symptoms of DII should refrain from further diving because response to therapy for future episodes is generally relatively poor. Victims of DII must have long-term follow-up.


Bladder Artery Embolization for Massive Hematuria Treatment in a Patient With Ataxia-Telangiectasia Acute Lymphoblastic Leukemia.
Ataxia-telangiectasia (AT) is a hereditary recessive autosomal disorder following a course of progressive cerebellar ataxia, and oculocutaneous telangiectasia. Disease-specific telangiectasias are generally localized in the oculocutaneous region, while telangiectasias located within the bladder are rarely seen in patients with AT. The patient who had been followed-up with a diagnosis of AT since the age of 3 years was later diagnosed with acute lymphoblastic leukemia at the age of 8 years. The patient developed hematuria approximately in the 29th month of treatment. The cystoscopy revealed regions of extensive hemorrhagic telangiectasis, which was interpreted as the bladder involvement of AT. The case presented here underwent several cycles of intravesical steroid and tranexamic acid treatments and intravesical cauterization procedures, but the patient was unresponsive to all medical treatment approaches. The patient was consequently evaluated by an interventional radiology unit for a selective arterial embolization. The patient's hematuria resolved after embolization. Bladder wall telangiectasia may, on rare occasions, develop in patients with AT, and can result in life-threatening hemorrhages. We also suggest that a selective arterial embolectomy can be safely carried out in pediatric patients with treatment-resistant intravesical bleeding.


Percutaneous handling of coronary lesions >20mm through stents. Is there a first choice strategy?
OBJECTIVE - This study compared the early and late results of the use of one single stent with those of the use of multiple stents in patients with lesions longer than 20mm. METHODS - Prospective assessment of patients electively treated with stents, with optimal stent deployment and followed-up for more than 3 months. From February '94 to January '98, 215 patients with lesions >20mm were treated. These patients were divided into 2 groups as follows: Group A - 105 patients (49%) with one stent implanted; Group B - 110 patients (51%) with multiple stents implanted. RESULTS - The mean length of the lesions was 26mm in group A (21-48mm) versus 29mm in group B (21-52mm) (p=0.01). Major complications occurred in one patient (0.9%) in group A (subacute thrombosis, myocardial infarctionand death) and in 2 patients (1.8%) in group B (one emergency surgery and one myocardial infarction) (p=NS). The results of the late follow-up period (>6 months) were similar for both groups (group A = 82% vs group B = 76%; p=NS), and we observed an event-free survical in 89% of the patients in group A and in 91% of the patients in group B (p=NS). Angina (group A = 11% vs group B = 7%) and lesion revascularization (group A = 5% vs group B = 6%; p=NS) also occurred in a similar percentage. No infarction or death was observed in the late follow-up period; restenosis was identified in 33% and 29% of the patients in groups A and B, respectively (p=NS). CONCLUSION - The results obtained using one stent and using multiple stents were similar; the greater cost-effectiveness of one stent implantation, however, seems to make this strategy the first choice.


Chronic nausea and vomiting: evaluation and treatment.
Nausea is an uneasy feeling in the stomach while vomiting refers to the forceful expulsion of gastric contents. Chronic nausea and vomiting represent a diverse array of disorders defined by 4 weeks or more of symptoms. Chronic nausea and vomiting result from a variety of pathophysiological processes, involving gastrointestinal and non-gastrointestinal causes. The prevalence of chronic nausea and vomiting is unclear, although the epidemiology of specific conditions, such as gastroparesis and cyclic vomiting syndrome, is better understood. The economic impact of chronic nausea and vomiting and effects on quality of life are substantial. The initial diagnostic evaluation involves distinguishing gastrointestinal causes of chronic nausea and vomiting (e.g., gastroparesis, cyclic vomiting syndrome) from non-gastrointestinal causes (e.g., medications, vestibular, and neurologic disorders). After excluding anatomic, mechanical and biochemical causes of chronic nausea and vomiting, gastrointestinal causes can be grouped into two broad categories based on the finding of delayed, or normal, gastric emptying. Non-gastrointestinal disorders can also cause chronic nausea and vomiting. As a validated treatment algorithm for chronic nausea and vomiting does not exist, treatment should be based on a thoughtful discussion of benefits, side effects, and costs. The objective of this monograph is to review the evaluation and treatment of patients with chronic nausea and vomiting, emphasizing common gastrointestinal causes.


Intramedullary nails versus distal locking plates for fracture of the distal femur: results from the Trial of Acute Femoral Fracture Fixation (TrAFFix) randomised feasibility study and process evaluation.
This feasibility study and process evaluation assessed the likely success of a definitive trial of intramedullary fixation with locked retrograde nails versus extramedullary fixation with fixed angle plates for fractures of the distal femur. A multicentre, parallel, two-arm, randomised controlled feasibility study with an embedded process evaluation was conducted at seven NHS hospitals in England. Treatment was randomly allocated in 1:1 ratio, stratified by centre and chronic cognitive impairment. Participants, but not surgeons or research staff, were blinded to the allocation. Patients 18 years and older with a fracture of the distal femur, who their surgeon believed would benefit from internal fixation, were eligible to take part.Participants were allocated to receive either a retrograde intramedullary nail or an anatomical locking plate. The primary outcomes for this feasibility study were the recruitment rate and completion rate of the EQ-5D-5L at 4 months post-randomisation. Baseline characteristics, disability rating index, quality of life scores, measurements of social support and self-efficacy, resource use and radiographic assessments were also collected. The views of patients and staff were collected during interviews. Recruitment and data completion were lower than expected. 23 of 82 eligible patients were recruited (nail, 11; plate, 12). The recruitment rate was estimated as 0.42 (95% CI 0.27 to 0.62) participants per centre-month. Data completeness of the EQ-5D-5L at 4 months was 61 per cent (95% CI 43% to 83%). The process evaluation demonstrated that the main barriers to recruitment were variation in treatment pathways across centres, lack of surgeon equipoise and confidence in using both interventions and newly formed research cultures that lacked cohesion. A modified trial design, with embedded recruitment support intervention, comparing functional outcome in cognitively intact adults who have sustained a fragility fracture of the distal femur is feasible. The Wales Research Ethics Committee 5 approved the study (ref: 16/WA/0225). ISRCTN92089567; Pre-results.


Vagus Nerve Stimulation and Other Neuromodulation Methods for Treatment of Traumatic Brain Injury.
The objective of this paper is to review the current literature regarding the use of vagus nerve stimulation (VNS) in preclinical models of traumatic brain injury (TBI) as well as discuss the potential role of VNS along with alternative neuromodulation approaches in the treatment of human TBI. Data from previous studies have demonstrated VNS-mediated improvement following TBI in animal models. In these cases, VNS was observed to enhance motor and cognitive recovery, attenuate cerebral edema and inflammation, reduce blood brain barrier breakdown, and confer neuroprotective effects. Yet, the underlying mechanisms by which VNS enhances recovery following TBI remain to be fully elucidated. Several hypotheses have been offered including: a noradrenergic mechanism, reduction in post-TBI seizures and hyper-excitability, anti-inflammatory effects, attenuation of blood-brain barrier breakdown, and cerebral edema. We present other potential mechanisms by which VNS acts including enhancement of synaptic plasticity and recruitment of endogenous neural stem cells, stabilization of intracranial pressure, and interaction with the ghrelin system. In addition, alternative methods for the treatment of TBI including deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, and focused ultrasound stimulation are discussed. Although the primary source data show that VNS improves TBI outcomes, it remains to be determined if these findings can be translated to clinical settings.


Pediatric AIDS: prevention of HIV infection in infants and children.
The Centers for Disease Control reported that 109,167 cases of AIDS had been diagnosed since 1981 and that approximately 40,000 persons were living with AIDS at the time of this writing. These numbers, however, are the tip of an iceberg that consists of approximately 1.5 million Americans who are infected by the human immunodeficiency virus (HIV). As we described in earlier articles of this series, the HIV infection/AIDS epidemic has invaded the domain of the American family through heterosexual transmission, vertical transmission, drug abuse, and sexual abuse of children. Therefore, physicians for children are now facing the prospects of having to deal with this disease in their practices. If there is something unique about pediatrics and other specialties of the medical profession dealing with infants and children, it is that "prevention" of disease can be and has been used effectively. One only needs to remember the 1950s, when the poliomyelitis epidemic was causing the same, if not greater, concerns in the lives of the American families. The development and application of the "polio" vaccines has virtually eliminated the threat of poliomyelitis in our society. Similarly, the incidence of diphtheria, tetanus, and smallpox has decreased to the point that these diseases present practically no threat to the US population. Armed with these positive experiences, we need to examine what we can do today to curb the spread of the HIV infection/AIDS among infants and children, and by extension, among the general population of our country.