Effect of a patellar realignment brace on patellofemoral relationships: evaluation with kinematic MR imaging.
The effect of a newly developed patellar realignment brace was evaluated in 21 patellofemoral joints (19 patients) with patellar subluxation (13 joints with lateral subluxation and eight with medial subluxation) by using active-movement, loaded kinematic magnetic resonance (MR) imaging. Sixteen patellofemoral joints (76%) demonstrated a qualitative correction of or improvement in patellar subluxation (ie, centralization of the patella or a decrease in the displacement of the patella) after application of the brace. Four of the five "failures" occurred in patellofemoral joints that had patella alta and/or dysplastic bone anatomy. These results indicate that the patellar realignment brace was able to counteract patellar subluxation in the majority of patellofemoral joints studied, as shown by active-movement, loaded kinematic MR imaging. This brace appears to be useful for conservative treatment of patients with patellofemoral joint pain secondary to patellar malalignment and maltracking.


Detection of the genial spinal canal in atrophic mandibles with a CBCT: a cadaver study.
The use of a single midline implant to retain a complete mandibular denture when more implants cannot be used is an incipient treatment modality. However, in the mandibular symphysis, the genial spinal canal (GSC) is an anatomical structure with neurovascular content that can be harmed during dental implant surgery. The purpose of the present study was to use CBCT of edentulous atrophic cadaver mandibles and evaluate how often the simulated placement of a single midline implant would contact the GSC if present. CBCT scans of 47 edentulous cadaver mandibles were performed. A digital simulation of the placement of a single midline implant (3.8 × 11.0 mm) was performed, and the implant-GSC contact was evaluated. A GSC was detected in the CBCT scan of all atrophic mandibles. In 42 cases (89.4%), the single midline implant contacted the GSC. On average, the five cases without GSC contact had a higher alveolar ridge (4.1 mm) and a lower GSC (0.79 mm) than did the cases with GSC contact. CBCT scans can adequately detect the GSC during pre-surgical diagnostics. There is a high risk of implant-GSC contact during surgery of the anterior mandible. However, the clinical relevance of such a contact is not known yet, because none of the clinical studies evaluating a single midline implant has reported any implant-GSC contact-related complications.


Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA.
Serotonin is involved in psychiatric disorders exhibiting abnormal prefrontal cortex (PFC) function (e.g. major depression, schizophrenia). We examined the effect of the stimulation of the dorsal and median raphe nuclei (DR and MnR, respectively) on the activity of PFC neurons. Electrical stimulation of DR/MnR inhibited 66% (115/173) of pyramidal neurons in the medial PFC (mPFC). The rest of the cases exhibited orthodromic excitations, either pure (13%) or preceded by short-latency inhibitions (20%). Excited neurons had a lower pre-stimulus firing rate than those inhibited. Excitations evoked by MnR stimulation had a shorter latency than those evoked by DR stimulation. WAY-100635 [a 5-hydroxytryptamine1A (5-HT1A) antagonist] and the selective gamma aminobutyric acidA (GABAA) antagonist picrotoxinin partially antagonized DR/MnR-evoked inhibitions, suggesting the involvement of 5-HT1A- and GABAA-mediated components. The presence of a direct DR/MnR-mPFC GABAergic component is suggested by the short latency of evoked inhibitions (9 +/- 1 ms), faster than those evoked in the secondary motor area (20 +/- 3 ms), and that of antidromic spikes evoked by DR/MnR stimulation in mPFC pyramidal neurons (15 +/- 1 ms). Stimulation of the DR/MnR with paired pulses enhanced the duration of inhibitions and turned some excitations into inhibitions. Thus, the DR/MnR control the activity of mPFC pyramidal neurons in vivo in a complex manner, involving 5-HT-mediated excitations and GABA- and 5-HT-mediated inhibitions.


Respiratory drive and timing during assisted ventilation in dogs.
In 8 anesthetized dogs, during isocapnic hyperoxia we studied the effect of assisted ventilation (AV) on ventilatory drive, inspiratory off-switch volume (Voff) and duration of inspiratory diaphragmatic activity (Tdi). Tidal volumes (Vt) during AV were double spontaneous Vt. Two electrodes were inserted in the diaphragm to obtain the electromyogram (EMG). The index of ventilatory drive was the EMG 0.3--i.e., the amplitude of the moving average EMG 300 ms after the onset of inspiratory activity. AV decreased EMG 0.3 but had no effect on Voff and Tdi. Vagotomy not only abolished the reduction in drive, but may have increased drive during AV.


Comorbidities and risk of mortality in patients with sleep apnea.
A variety of disorders, most notably cardiovascular diseases, was linked to sleep apnea (SA), but their impact on mortality of SA patients had not been systematically investigated. We aimed to develop a composite index based on the comorbidity burden to predict mortality risk. Using Taiwan National Health Insurance Research Database, 9853 adult SA patients were enrolled and their comorbidity profile at baseline was recorded. The subjects were followed from 1995 till death or the end of 2011. A Cox regression model was used for multivariable adjustment to identify independent predictors for mortality. During an average follow-up period of 5.3 ± 3.1 years, 311 (3.2%) subjects died. SA patients with any comorbidity had a higher risk for death compared to those without comorbidity (HR: 11.01, 95% CI 4.00-30.33, p < 0.001). Age and 10 comorbidities related to increased overall mortality were identified, from which the CoSA (Comorbidities of Sleep Apnea) index was devised. The corresponding hazard ratios for patients with CoSA index scores of 0, 1-3, 4-6, and >6 were 1 (reference), 3.29 (95% CI, 2.04-5.28, p < 0.001), 13.56 (95% CI, 8.63-21.33, p < 0.001), and 38.47 (95% CI, 24.92-59.38, p < 0.001), respectively. Based on the comorbidity burden, we developed an easy-to-use tool to evaluate mortality risk in SA. Key messages: Sleep apnea (SA) is linked to a variety of disorders, particularly cardiovascular diseases. SA patients with any comorbidity may experience a higher risk of death in comparison to those without comorbidity. Comorbidities related to increased mortality are identified and converted into a simple risk indicator, the CoSA (Comorbidities of Sleep Apnea) index scores, which may help to stratify risk of death in daily practice.


Expression of VGF mRNA in the adult rat central nervous system.
VGF is a secretory peptide precursor that is expressed and processed by neuronal cells in a cell type-specific fashion. In addition, VGF transcription and secretion are rapidly and relatively selectively induced by neurotrophins and depolarization in vitro. To gain insight into the possible function(s) of VGF in the nervous system, we have carried out a detailed examination of the distribution of VGF mRNA in the adult rat central nervous system by using in situ hybridization. Robust expression was detected in many neurons throughout the brain and spinal cord, in several types of neurons in the retina, and in presumptive chromaffin cells of the adrenal medulla. In the brain, prominent expression of VGF mRNA was observed in neurons of the main and accessory olfactory bulbs; in the anterior olfactory nucleus; in the induseum griseum and taenia tecta; in the olfactory tubercle; in CA1-CA3, the hilus of the dentate gyrus, and the subicular complex of the hippocampal formation; in the piriform, periamygdaloid, transitional, and lateral entorhinal cortices; in the endopiriform nucleus; in the hypothalamus, particularly the preoptic, periventricular, supraoptic, suprachiasmatic, and arcuate nuclei; and in a number of septal, thalamic, amygdaloid, and brainstem nuclei. Labeling was also seen in neurons of the neocortex and transitional cortical areas, particularly in layer V, and in basal ganglia and cerebellum. These data demonstrate that VGF mRNA is expressed much more extensively in the brain than has been described in previous RNA or immunohistochemical studies, and, furthermore, that VGF is widely expressed in the spinal cord and retina.


Sleep-Disordered Breathing in Heart Failure - A Therapeutic Dilemma.
Sleep-disordered breathing (SDB) occurs in approximately 50% of patients with reduced left ventricular ejection fraction receiving contemporary heart failure (HF) therapies. Obstructive (OSA) and central sleep apneas (CSA) interrupt breathing by different mechanisms but impose qualitatively similar autonomic, chemical, mechanical, and inflammatory burdens on the heart and circulation. Because contemporary evidence-based drug and device HF therapies have little or no mitigating effect on the acute or long-term consequences of such stimuli, there is a sound mechanistic rationale for targeting SDB to reduce cardiovascular event rates and prolong life. However, the promise of observational studies and randomized trials of small size and duration describing a beneficial effect of treating SDB in HF via positive airway pressure was not realized in 2 recent randomized outcome-driven trials: SAVE, which evaluated the cardiovascular effect of treating OSA in a cohort without HF, and SERVE-HF, which reported the results of a strategy of random allocation of minute-ventilation-triggered adaptive servo-ventilation (ASV) for HF patients with CSA. Whether effective treatment of either OSA or CSA improves the HF trajectory by reducing cardiovascular morbidity or mortality has yet to be definitively established. ADVENT-HF, designed to determine the effect of treating both CSA and non-sleepy OSA HF patients with a peak-airflow triggered ASV algorithm, could resolve this present clinical equipoise concerning the treatment of SDB.


The effectiveness of an individualized form of day hospital treatment.
The traditional group format of day hospital treatment for eating disorders restricts individual tailoring of treatment, which is challenging when complex cases are referred. In 2007 we introduced a new program that included individual sessions. Patients referred to this program were older, had longer illness duration, and more pre-treatment symptoms than the original group program. These clients also had more psychopathology, and were more likely to have a diagnosis of anorexia nervosa binge/purge subtype. Weight gain and abstinence from symptoms were less likely for patients in this new program. However, premature discharge, rapid response, symptom frequencies, and relapse rates did not differ.


[Study on terahertz spectroscopy of Hotan jade].
Terahertz time-domain spectroscopy (THz-TDS) technique has a wide range of applications including illicit drugs and explosive detection, and organic molecules recognition. In the present paper, the spectral features of three kinds of Hotan jade were studied experimentally by THz-TDS technique and the characteristic absorption spectra and refractive index were obtained in the range of 0.2 to 2.6 THz. The experimental results show that different samples have different absorption characters, and the refractive index is 2.4-2.7 in the range of 0.2-2.6 THz. The results indicate that it is feasible to apply THz-TDS technique to identification of Hotan jade, which provides a new approach to the nondestructive examination of Hotan jade.


Characterization of DSM-IV Opioid Dependence Among Individuals of European Ancestry.
The opioid epidemic in the United States has led to unprecedented increases in morbidity and mortality, posing a serious public health crisis. Although twin and family studies, as well as genome-wide association studies (GWAS), all identify significant genetic factors contributing to opioid dependence, no studies to date have estimated marker-based heritability estimates of opioid dependence. The goal of the current study was to use a large, genetically imputed, case/control sample of 4,064 participants (after quality control and imputation) with genome-wide data to estimate the unbiased heritability tagged by single nucleotide polymorphisms (SNPs). Study data were part of the Genome-wide Study of Heroin Dependence obtained via the Database for Genotypes and Phenotypes (dbGaP). Genomic-Relatedness-Matrix Restricted Maximum Likelihood with adjustment for minor allele frequency (MAF) and linkage disequilibrium (LD; GREML-LDMS) was used to determine the variation in opioid dependence attributable to common SNPs from imputed data. Mixed linear models were used in an exploratory GWAS to assess effects of single SNPs. At least 45% of the variance in opioid dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, was attributable to common SNPs, after stratifying to account for differences in MAF and LD across the genome. Most of the genetic variance was tagged by SNPs in the 1%-9% MAF range and in low LD with other SNPs in the region. Two markers in LOC101927293 survived multiple-testing correction (i.e., q value < .05). Nearly half of the variation in opioid dependence can be attributed to common SNPs. Most of this variation is due to rare variants in low LD with other markers in the region.


Anti-inflammatory effect of avenanthramides via NF-κB pathways in C2C12 skeletal muscle cells.
Avenanthramides (Avns), the polyphenol compounds found only in oats, have been shown to exhibit anti-inflammatory effects mainly by inhibiting nuclear factor (NF)-κB activation in select cell lines. However, the molecular mechanism by which Avns regulate the NF-κB pathway is still unclear. The purpose of this study was to investigate (1) the molecular mechanism by which three main fractions of Avns (AvnA, AvnB and AvnC) interact with IκB Kinase β (IKKβ); and (2) whether this interaction results in reduced inflammatory responses in skeletal muscle cells. The protein-ligand docking and molecular dynamics simulation studies suggest that Avns acted as an allosteric inhibitor for modulating IKKβ's affinity for the NF-κB complex. Thus, Avns reduced IKKβ kinase activity in response to tert-butyl hydroperoxide (tBHP) stimulation and attenuated tBHP-induced TNFα and IL-1β mRNA expression. Furthermore, the three-fold increases in cyclooxygenase-2 (COX-2) protein and luciferase activity with tBHP treatment were reduced by 50% with Avns (P < .01), along with decreased prostaglandin E2 levels (P < .01). These data indicate that Avns are potent inhibitors of NFκB-mediated inflammatory response due to the downregulation of IKKβ activity in C2C12 cells.


Music-based intervention drives paretic limb acceleration into intentional movement frequencies in chronic stroke rehabilitation.
This study presented a novel kinematic assessment of paretic limb function "online" during the actual therapeutic exercisers rooted within the acceleration domain. Twenty-eight patients at chronic stroke stages participated in an auditory-motor intervention mapping reaching movements of the paretic arm unto surfaces of large digital musical instruments and sound tablets that provided rhythmic entrainment cues and augmented auditory feedback. Patients also wore a tri-axial accelerometer on the paretic limb during the nine-session intervention. The resulting acceleration profiles were extracted and quantified within the frequency domain. Measures of peak power and peak width were leveraged to estimate volitional control and temporal consistency of paretic limb movements, respectively. Clinical assessments included the Wolf Motor Function Test and Fugl-Meyer - Upper Extremity subtest. The results showed that peak power increased significantly from Session 1 to Session 9 within oscillatory frequency ranges associated with intentional movement execution (i.e., 4.5 Hz). Decreases in peak width over time provided additional evidence for improved paretic arm control from a temporal perspective. In addition, Peak width values obtained in Session 1 was significantly correlated with pre-test Fugl-Meyer - Upper Extremity scores. These results highlighted improvements in paretic limb acceleration as an underlying mechanism in stroke motor recovery and shed further light on the utility of accelerometry-based measures of paretic limb control in stroke rehabilitation. The data reported here was obtained from a larger clinical trial: https://clinicaltrials.gov/ct2/show/NCT03246217 ClinicalTrials.gov Identifier: NCT03246217.


Development of the full-length cDNA clones of two porcine epidemic diarrhea disease virus isolates with different virulence.
The recently emerged highly virulent variants of porcine epidemic and diarrhea virus (PEDV) remain a huge threat to the worldwide swine industry. Here, we describe the development of a bacterial artificial chromosome (BAC) reverse genetics system for PEDV based on two recent Chinese field isolates, namely CHM2013 and BJ2011C. Phylogenetically, CHM2013 is closely related to the vaccine strain SM98 whereas the isolate BJ2011C belongs to the GIIb group, a cluster that contains many recent pandemic strains. The full-length cDNA clones of the two isolates were constructed into BAC under the control of CMV promoter. The rescued viruses rBJ2011C and rCHM2013 were found to replicate at the kinetics similar to their respective parental viruses in cell culture. When tested in the 2-day-old pig model, rBJ2011C caused severe diarrhea of piglets with extensive damages to the intestinal epithelium, leading to 100% fatality within 48 hours. In contrast, the rCHM2013-inoculated piglets all survived with only very minor tissue damage observed. Thus, we have successfully established a convenient platform for PEDV genome manipulation. This study also represents the first description of a DNA-launched reverse genetics system for the highly virulent PEDV.


Characterization of decay-accelerating factor (DAF) in human skin.
Decay-accelerating factor (DAF) is a 70-kD membrane glycoprotein that regulates autologous complement activation, by preventing assembly of alternative or classical C3/C5 convertases, and has been shown to have a wide tissue distribution. In this study, DAF antigen has been demonstrated at the intercellular spaces of normal human epidermis with monoclonal antibody against DAF using the peroxidase-anti-peroxidase method. The amount of DAF was greater at the granular layer than the basal cell layer as judged by intensity of the staining. Western blot analysis of DAF in the epidermis showed a 55-kD band, whereas that of buffy coat cells was approximately 67 kD. When DAF of the epidermis was treated with neuraminidase, the molecular weight was reduced to 53 kD, whereas that of buffy coat cells was 56 kD. These results indicated that the content of sialic acid of DAF in the epidermis was different from that of buffy coat cells. In phosphatidylinositol-specific phospholipase C (PIPLC)-treated normal human skin, DAF was not demonstrated in the epidermis, whereas DAF remained unchanged on the elastic fibers. After the treatment of the epidermis by PIPLC, DAF was released into the buffer shown by Western blot analysis. These results suggested that DAF on the epidermis was anchored to keratinocyte via phosphatidylinositol (PI), whereas the anchoring mechanism of DAF on the elastic fibers was not through PI.


Non-overlapping factor scales for the Mini-Mult.
Performed a principal axes factor analysis on Mini-Mult item data obtained from 249 medical and psychiatric patients. Six factors were extracted and after Varimax rotation were labeled Psychoticism, Alienation and Low Morale, Somatization, Shyness, Dysphoria, and Defensiveness. Corresponding to these factors, non-overlapping summative scales were constructed and their reliabilities evaluated. Alpha coefficients were satisfactory for three scales, but the remaining scales, which contained fewer items, had less adequate reliabilities. The scales were recommended for applications in which it is desirable to avoid the excessive item overlap of the standard Mini-Mult scales.


Rapid nuclear transit and impaired degradation of amyloid β and glypican-1-derived heparan sulfate in Tg2576 mouse fibroblasts.
Anhydromannose (anMan)-containing heparan sulfate (HS) derived from S-nitrosylated glypican-1 is generated in endosomes by an endogenously or ascorbate induced S-nitrosothiol-catalyzed reaction. Expression and processing of amyloid precursor protein (APP) is required to initiate formation and endosome-to-nucleus translocation of anMan-containing HS in wild-type mouse embryonic fibroblasts (WT MEF). HS is then transported to autophagosomes and finally degraded in lysosomes. To investigate how APP-derived amyloid β (Aβ) peptide affects intracellular trafficking of HS, we have studied nuclear transit as well as autophagosome/lysosome targeting and degradation in transgenic Alzheimer disease mouse (Tg2576) MEF which produce increased amounts of Aβ. Deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody showed anMan staining in the nuclei of Tg2576 MEF after 5 min of ascorbate treatment and after 15 min in WT MEF. There was also greater nuclear accumulation of HS in Tg2576 MEF as determined by (35)S-sulfate-labeling experiments. Tg2576 MEF was less sensitive to inhibition of NO production and copper-chelation than WT MEF. By using APP- and Aβ-recognizing antibodies, we observed nuclear translocation of Aβ peptide in Tg2576 MEF but not in WT MEF. HS remained in the nucleus of WT MEF for at least 8 h and was then transported to autophagosomes. By 8 h, HS had disappeared from the nuclei of Tg2576 MEF but colocalized poorly with the autophagosome marker LC3. Aβ also disappeared rapidly from the nuclei of Tg2576 MEF. Initially, it appeared in acidic vesicles and later it accumulated extracellularly. Thus, in Tg2576 MEF there is nuclear accumulation as well as secretion of Aβ and impaired degradation of HS.


Donor sperm production in heterologous recipients by testis germ cell transplantation in the dromedary camel.
The object of this study was to investigate if testis germ cell transplantation (TGCT) into a heterologous recipient would result in donor-origin spermatogenesis in the dromedary camel. First, we investigated a workable protocol for TGCT in camels, including donor cell isolation, enrichment by density gradient centrifugation (Percoll and Bovicoll), rete testis injection and microsatellite detection of donor and recipient genotypes. Second, the effects of three doses of Dolichos biflorus agglutinin (DBA), a glycoprotein that specifically binds to gonocytes or Type A spermatogonia, on testis germ cell depletion were investigated by direct injection into the rete testis of a male camel. Seven recipients were prepared with DBA treatment, two males were castrated at 4 weeks for depletion assessment and the remaining five received donor cells 4-6 weeks after treatment. On average, ~17 million cells were isolated per gram of testis tissue, with 19.5±1.9% DBA-positive (DBA+) cells. Percoll centrifugation yielded a 1.5-fold increase in DBA+ cells while Bovicoll centrifugation produced a 2.5-fold increase from the input cells of 18.6±2.1% DBA+ cells. Semen was collected from the recipients 13-20 weeks after transfer and the presence of donor DNA in the samples was determined using microsatellite markers. In two of the five recipients, all semen samples were shown to be positive for donor-derived cells. These results demonstrate for the first time that: (1) heterologous testicular germ cell transplantation in camels is feasible and the recipients are able to produce spermatozoa of donor origin and (2) DBA can be used effectively to deplete endogenous stem cells.


A comparison of radiologic methods in the diagnosis of renal mass lesions.
The reliability of radiologic diagnosis was studied in 99 patients undergoing ultrasonography, computerized tomography and angiography in work up of renal mass lesions. The diagnoses were confirmed by angiography combined with percutaneous puncture or by surgery. Of the lesions, 37 were simple renal cysts and 56 were renal cell carcinomas. Eighty-eight percent were diagnosed correctly by ultrasonography, 96% by computerized tomography and 84% by angiography. The conclusion is that the radiologic evaluation of a renal mass lesion found at urography should start with ultrasonography. Percutaneous puncture is not recommended if all criteria of a simple renal cyst are strictly fulfilled at ultrasonography. In all other cases a computerized tomography is thought to be mandatory to avoid false negative diagnoses of malignant tumours or other diseases which may need therapy. In some patients a combination with angiography and percutaneous puncture is advised to establish a diagnosis prior to surgery.


Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease.
The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted.


Mistuning in two-part singing.
This research describes the strategy of singers in reacting to the pitch deviation from equally tempered (ET) value in their ensemble partner's part in singing two-part a cappella music, and the ability of professional musicians to identify such deviations. Professional singers preferred to maintain the purity of melodic intervals in their own part and to ignore the occurring harmonic mistuning with their deviating ensemble partner. In multi-part singing, the musical interval perception ability of the singers is more finely honed for production than it is for perception, which can be explained by the enhancing effect of the memory of how to vocally produce the intervals, available only in the process of singing.


Interaction effects of epidemiologic factors in the feline urological syndrome.
Disease-associated factors are most often evaluated individually, while as disease determinants they act in mutual combinations. Applying simple epidemiologic methods, the present study evaluates the effect on occurrence of the Feline Urological Syndrome (FUS) of combining categories within sex, diet and activity. Some factor interactions could be described as additive, while certain combinations acted in a synergistic fashion. The apparent overall effect which might be explained by the excess-risk categories within these three factors was found to account for approximately 90% of the total occurrence of FUS in the population at risk. As a further result of the epidemiologic methods applied, a possible pathogenesis is outlined. It involves relative impairment of kidney function affected through two pathways: increased kidney working load and decreased kidney capability, both associated in various ways with castration, high levels of dry cat foods, and indoor confinement.


[Anticoagulation Therapy in Atrial Fibrillation and Congestive Heart Failure].
Modern data on the need to appoint oral anticoagulants in patients with atrial fibrillation and concomitant heart failure. Based on the Phase III study analysis comparing the direct oral anticoagulant warfarin and meta-analysis shows that taking direct oral coagulants no less effective and safer than warfarin in patients with atrial fibrillation and heart failure, which affects significantly fewer intracranial and heavy bleeding.


Diversity of Wolbachia endosymbionts in heteropteran bugs.
An extensive survey of Wolbachia endosymbionts in Japanese terrestrial heteropteran bugs was performed by PCR detection with universal primers for wsp and ftsZ genes of Wolbachia, cloning of the PCR products, restriction fragment length polymorphism analysis of infecting Wolbachia types, and molecular phylogenetic characterization of all the detected Wolbachia strains. Of 134 heteropteran species from 19 families examined, Wolbachia infection was detected in 47 species from 13 families. From the 47 species, 59 Wolbachia strains were identified. Of the 59 strains, 16 and 43 were assigned to A group and B group in the Wolbachia phylogeny, respectively. The 47 species of Wolbachia-infected bugs were classified into 8 species with A infection, 28 species with B infection, 2 species with AA infection, 3 species with AB infection, 5 species with BB infection, and 1 species with ABB infection. Molecular phylogenetic analysis showed little congruence between Wolbachia phylogeny and host systematics, suggesting frequent horizontal transfers of Wolbachia in the evolutionary course of the Heteroptera. The phylogenetic analysis also revealed several novel lineages of Wolbachia. Based on statistical analyses of the multiple infections, we propose a hypothetical view that, in the heteropteran bugs, interactions between coinfecting Wolbachia strains are generally not intense and that Wolbachia coinfections have been established through a stochastic process probably depending on occasional horizontal transfers.


Canine transposition as autosomal recessive trait in an inbred kindred.
Three cases of bilateral transposition of maxillary canines with premolars were observed among eight siblings, Investigation of the sibship revealed consanguinity of the parents (cousins twice removed). Analysis of the extensive pedigree showed an hereditary pattern typical of autosomal recessive traits.


Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases: A Proposal of Risk Stratification and Identification of a Synaptophysin-positive Aggressive Subset.
Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P<0.001). Four tumors (6.4%) expressed synaptophysin, which all belonged to the high-risk group and pursued an aggressive course. The present study demonstrated the independent prognostic significance of large tumor size and atypical histology in EHE, as well as the value of risk stratification using these 2 factors. Moreover, we revealed a small EHE subset with aberrant synaptophysin expression, which may have potential prognostic and diagnostic implications.


Strategy for chemotherapeutic delivery using a nanosized porous metal-organic framework with a central composite design.
Enhancing drug delivery is an ongoing endeavor in pharmaceutics, especially when the efficacy of chemotherapy for cancer is concerned. In this study, we prepared and evaluated nanosized HKUST-1 (nanoHKUST-1), nanosized metal-organic drug delivery framework, loaded with 5-fluorouracil (5-FU) for potential use in cancer treatment. NanoHKUST-1 was prepared by reacting copper (II) acetate [Cu(OAc)2] and benzene-1,3,5-tricarboxylic acid (H3BTC) with benzoic acid (C6H5COOH) at room temperature (23.7°C±2.4°C). A central composite design was used to optimize 5-FU-loaded nanoHKUST-1. Contact time, ethanol concentration, and 5-FU:material ratios were the independent variables, and the entrapment efficiency of 5-FU was the response parameter measured. Powder X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption were used to determine the morphology of nanoHKUST-1. In addition, 5-FU release studies were conducted, and the in vitro cytotoxicity was evaluated. Entrapment efficiency and drug loading were 9.96% and 40.22%, respectively, while the small-angle X-ray diffraction patterns confirmed a regular porous structure. The SEM and TEM images of the nanoHKUST-1 confirmed the presence of round particles (diameter: approximately 100 nm) and regular polygon arrays of mesoporous channels of approximately 2-5 nm. The half-maximal lethal concentration (LC50) of the 5-FU-loaded nanoHKUST-1 was approximately 10 µg/mL. The results indicated that nanoHKUST-1 is a potential vector worth developing as a cancer chemotherapeutic drug delivery system.


The wide spectrum of COVID-19 neuropsychiatric complications within a multidisciplinary centre.
A variety of neuropsychiatric complications has been described in association with COVID-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with COVID-19 seen in a multidisciplinary hospital centre over 6 months. We conducted a retrospective, observational study of all patients showing neurological or psychiatric symptoms in the context of COVID-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris-Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of COVID-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 COVID-19 patients with a de novo neurological or psychiatric manifestation were included in the database and 245 were included in the final analyses. One-hundred fourteen patients (47%) were admitted to the intensive care unit and 10 (4%) died. The most frequent neuropsychiatric complications diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%) and cerebrovascular disorders (16%). No patients showed CSF evidence of SARS-CoV-2. Encephalopathy was associated with older age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the intensive care unit. The majority of these neuropsychiatric complications could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders.


Corynebacterium atrinae sp. nov., isolated from the gastrointestinal tract of a pen shell, Atrina pectinata.
A novel Gram-stain-positive, non-motile, facultatively anaerobic and rod-shaped bacterium, strain PSPT56(T), was isolated from the gastrointestinal tract of a pen shell (Atrina pectinata). Optimal growth of strain PSPT56(T) was ascertained to occur at 30 °C, pH 8.0 and in the presence of 1-2 % (w/v) NaCl. The strain was catalase-positive and oxidase-negative. The major cellular fatty acids were C18 : 1ω9c, C16 : 0, C17 : 1ω8c and C17 : 0. Tuberculostearic acid was not present. The major cell-wall sugars were ribose, galactose, glucose and arabinose. Peptidoglycan amino acids were meso-diaminopimelic acid, alanine and glutamic acid. The predominant isoprenoid quinone was MK-8(H2). Strain PSPT56(T) contained phosphatidylglycerol, diphosphatidylglycerol, an unidentified phospholipid, two unidentified lipids and two unidentified amino-lipids. Mycolic acids were detected as constitutive components of the cell wall. A phylogenetic analysis based on 16S rRNA gene sequence similarity showed that strain PSPT56(T) was most closely related to Corynebacterium testudinoris M935/96/4(T) and Corynebacterium felinum M714/95/5(T) with 98.69 % and 97.01 % similarity, respectively. DNA-DNA hybridization experiments indicated less than 29.9 % relatedness to the phylogenetically closest species. The G+C content of genomic DNA was 67.6 mol%. The phenotypic, phylogenetic and genotypic analyses indicated that strain PSPT56(T) represents a novel species within the genus Corynebacterium, for which the name Corynebacterium atrinae is proposed. The type strain is PSPT56(T) ( = KACC 17525(T) = JCM 19266(T)).


Application of lymphocyte immunophenotyping in selected diseases.
The results of lymphocyte immunophenotyping in a variety of autoimmune disorders confirm major T cell immunoregulatory defects. The defects associated with autoreactive T cells appear to exist at the level/interface of the CD4 inducer of suppression and the CD8 effector cell. Although activated CD4 cells are occasionally found, subpopulations of activated CD8 cells are seen more commonly. A similar observation has been made in a subpopulation of patients with common variable hypogammaglobulinemia. In conjunction with antigen-specific T cell clones, we anticipate that flow cytometry will continue to aid in the further dissection of these HLA-restricted, anti-idiotype-controlled and pharmacological-mediated reactions. The known immunological distinction between AML and ALL are such that blast immunophenotyping will confirm and complement the clinical and morphological diagnosis in the vast majority of patients. With regards to chronic lymphocytosis in general and CLL in particular, flow cytometry offers an unusual opportunity to characterize lineage, monoclonality, stage of differentiation, presence or absence of activation antigens, aneuploidy and oncogene expression. Flow cytometry will continue to contribute to our understanding of the etiology and pathogenesis of CLL.


Origin of π-Facial Stereoselectivity in Thiophene 1-Oxide Cycloadditions.
We report a DFT computational study (M06-2X) of π-facial selectivity in the Diels-Alder reactions of thiophene 1-oxide. The preference for the syn cycloaddition arises because the ground state geometry of thiophene 1-oxide is predistorted into an envelope conformation that resembles the syn transition state geometry. The syn distortion occurs to minimize the effect of hyperconjugative antiaromaticity in the thiophene 1-oxide, arising from overlap of the σ*SO with the π-system. The syn selectivity follows through to the product structure that is stabilized by a π-σ*SO interaction, related to the 7-norbornenyl ion stability.


EXPRESSION OF GENETIC VARIATION IN BODY SIZE OF THE COLLARED FLYCATCHER UNDER DIFFERENT ENVIRONMENTAL CONDITIONS.
Heritability of body size in two experimentally created environments, representing good and poor feeding conditions, respectively, was estimated using cross-fostered collared flycatcher Ficedula albicollis nestlings. Young raised under poor feeding conditions attained smaller body size (tarsus length) than their full-sibs raised under good feeding conditions. Parent-offspring regressions revealed lower heritability (h2 ) of body size under poor than under good feeding conditions. Hence, as the same set of parents were used in the estimation of h2 in both environments, this suggests environment-dependent change in additive genetic component of variance (VA ), or that the genetic correlation between parental and poor offspring environment was less than that between parental and good offspring environment. However, full-sib analyses failed to find evidence for genotype-environment interactions, although the power of these tests might have been low. Full-sib heritabilities in both environments tended to be higher than estimates from parent-offspring regressions, indicating that prehatching or early posthatching common environment/maternal effects might have inflated full-sib estimates of VA . The effect of sibling competition on estimates of VA was probably small as the nestling size-hierarchy at day 2 posthatch was not generally correlated with size-hierarchy at fledging. Furthermore, there was no correlation between maternal body condition during the incubation and final size of offspring, indicating that direct maternal effects related to nutritional status were small. A review of earlier quantitative genetic studies of body size variation in birds revealed that in eight of nine cases, heritability of body size was lower in poor than in good environmental conditions. The main implication of this relationship will be a decreased evolutionary response to selection under poor environmental conditions. On the other hand, this will retard the loss of genetic variation by reducing the accuracy of selection and might help explain the moderate to high heritabilities of body-size traits under good environmental conditions.


Decomposition of jellyfish carrion in situ: Short-term impacts on infauna, benthic nutrient fluxes and sediment redox conditions.
Jellyfish often form blooms that persist for weeks to months before they collapse en masse, resulting in the sudden release of large amounts of organic matter to the environment. This study investigated the biogeochemical and ecological effects of the decomposition of jellyfish in a shallow coastal lagoon in New South Wales, Australia. Catostylus mosaicus carrion was added to the surface of shallow sub-tidal sediments and biogeochemical parameters and macrofaunal abundance immediately below the jellyfish carrion were measured over three days. Sediment plots without jellyfish served as controls. Sediment oxygen demand and carbon and nitrogen efflux increased by up to 60-fold in the jellyfish plots, compared to control plots, and dissolved organic nutrient fluxes were more sustained than in previous studies due to the use of fresh rather than frozen biomass. The decomposing jellyfish progressively altered sediment redox conditions, indicated by an increase in porewater iron (II) and sulfide concentrations measured by high-resolution in situ diffusive samplers. Abundance of some macrofaunal taxa in the jellyfish plots decreased relative to controls, however, the abundance of a carnivorous gastropod, which was presumably feeding on the carrion, increased in the jellyfish plots. While jellyfish carrion may be a food source for some macrofauna, low oxygen conditions coupled with the accumulation of toxic dissolved sulfides in the near-surface sediments may explain the overall change in the macroinfaunal community.


Anammox and denitrification separately dominate microbial N-loss in water saturated and unsaturated soils horizons of riparian zones.
Fertilized agroecosystems may show considerable leaching of the mobile nitrogen (N) compound NO3-, which pollutes groundwater and causes eutrophication of downstream waterbodies. Riparian buffer zones, positioned between terrestrial and aquatic environments, effectively remove NO3- and serve as a hotspot for N2O emissions. However, microbial processes governing NO3- reduction in riparian zones still remain largely unclear. This study explored the underlying mechanisms of various N-loss processes in riparian soil horizons using isotopic tracing techniques, molecular assays, and high-throughput sequencing. Both anaerobic ammonium oxidation (anammox) and denitrification activity were maximized in the riparian fringe rather than in the central zones. Denitrifying anaerobic methane oxidation (damo) process was not detected. Interestingly, both contrasting microbial habitats were separated by a groundwater table, which forms an important biogeochemical interface. Denitrification dominated cumulative N-losses in the upper unsaturated soil, while anammox dominated the lower oxic saturated soil horizons. Archaeal and bacterial ammonium oxidation that couple dissimilatory nitrate reduction to ammonium (DNRA) with a high cell-specific rate promoted anammox even further in oxic subsurface horizons. High-throughput sequencing and network analysis showed that the anammox rate positively correlated with Candidatus 'Kuenenia' (4%), rather than with the dominant Candidatus 'Brocadia'. The contribution to N-loss via anammox increased significantly with the water level, which was accompanied by a significant reduction of N2O emission (∼39.3 ± 10.6%) since N-loss by anammox does not cause N2O emissions. Hence, water table management in riparian ecotones can be optimized to reduce NO3- pollution by shifting from denitrification to the environmentally friendly anammox pathway to mitigate greenhouse gas emissions.


Proteomics in Drosophila melanogaster.
To be able to understand cellular mechanisms, we require fully integrated data sets combining information about gene expression, protein expression, post-translational modification states, sub-cellular location and complex formation. Proteomics is a very powerful technique that can be applied to interrogate changes at the protein level. Studying this effectively requires specialised facilities within research institutes. Here, we describe the setting up and operation of such a facility, providing a resource for the Arabidopsis and Drosophila research communities.


Bio-filtration capacity, oxygen consumption and ammonium excretion of Dosinia ponderosa and Chione gnidia (Veneroida: Veneridae) from areas impacted and non-impacted by shrimp aquaculture effluents.
Mollusks are some of the most important, abundant and diverse organisms inhabiting not only aquatic ecosystems, but also terrestrial environments. Recently, they have been used for bioremediation of aquaculture effluents; nevertheless, for that purpose it is necessary to analyze the capacity of a particular species. In this context, an experimental investigation was developed to evaluate the performance of two bivalves C. gnidia and D. ponderosa, collected from areas with or without shrimp aquaculture effluents. For this, the filtration capacity (as clearance rate) as well as the oxygen consumption and ammonia excretion rates were measured following standard methods. The clearance rate was significantly higher for D. ponderosa from impacted areas, when com- pared to C. gnidia, from both areas. Contrarily, the oxygen consumption was greater for C. gnidia from impacted areas compared to D. ponderosa from both areas. The same tendency was observed for the ammonia excretion with the highest rates observed for C. gnidia from impacted areas, whereas no differences were observed among D. ponderosa from both areas. The results suggest that both species developed different strategies to thrive and survive under the impacted conditions; D. ponderosa improved its filtration efficiency, while C. gnidia modified its oxygen consumption and ammonia excretion. We concluded that both species, and particularly D. ponderosa, can be used for bioremediation purposes.


The impact of waiting time on hearing outcome and patients' satisfaction after cholesteatoma surgery.
Cholesteatoma is a formation of epithelium mass in the middle ear. Surgery aims to prevent complications while maintain or improve hearing. To determine if waiting time until cholesteatoma surgery affects hearing outcome and patients' satisfaction. A retrospective cohort study performed at the only Ear Nose Throat clinic in one county in Sweden. Sixty concomitant surgeries, both first time and revisions, were included. Of the 60 surgeries, 33 (55%) were performed within a 3-month period. The mean waiting time was 1.4 months. In the remaining 27 cases, the mean waiting time was 8.6 months. Both groups had preoperatively similar air conduction pure tone average (AC PTA4), 47.3 dB and 47.0 dB respectively. The mean AC PTA4 gain was greater in the group with waiting time ≤3 months (8.6 dB) compared to the >3 months group (1.2 dB, p = 0.040). The patients' satisfaction was lower in the latter group, but the difference was not statistically significant. This study indicates that longer waiting time to cholesteatoma surgery has a negative impact on postoperative hearing results but not on patients' satisfaction. The outcome of this study suggests that waiting time to surgery can be a factor determining postoperative hearing results.


Palliative Radiotherapy for Leptomeningeal Carcinomatosis-Analysis of Outcome, Prognostic Factors, and Symptom Response.
Introduction: The purpose of this article is to report our institution's 10-year experience on palliative radiotherapy for the treatment of leptomeningeal carcinomatosis (LC), assessing survival, neurologic outcome, and prognostic factors. Patients and methods: We retrospectively analyzed 110 patients who received palliative radiotherapy for LC between 2008 and 2018. The most common histologies were breast cancer (n = 43, 39.1%) and non-small cell lung cancer (NSCLC) (n = 31, 28.2%). Radiotherapy was administered as whole-brain radiotherapy (WBRT) (n = 51, 46.4%), focal spinal RT (n = 11, 10.0%) or both (n = 47, 42.7%). Twenty-five patients (22.7%) were selected for craniospinal irradiation. Clinical performance and neurologic function were quantified on the neurologic function scale (NFS) before and in response to therapy. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for survival. Results: Ninety-eight patients (89.1%) died and 12 (10.9%) were alive at the time of analysis. Median OS from LC diagnosis and from the beginning of RT was 13.9 weeks (IQR: 7.1-34.0) and 9.9 weeks (IQR: 5.3-26.3), respectively. In univariate analysis, prognostic of longer OS were a Karnofsky performance scale index (KPI) of ≥70% (HR 0.20, 95%-CI: [0.13; 0.32], p < 0.001), initially moderate neurological deficits (NFS ≤2) (HR 0.32, 95% CI: [0.19; 0.52], p < 0.001), symptom response to RT (HR 0.41, 95%-CI: [0.26; 0.67], p < 0.001) and the administration of systemic therapy (HR 0.51, 95%-CI: [0.33; 0.78], p = 0.002). Prognostic of inferior OS were high-grade myelosuppression (HR 1.78, 95% CI: [1.06; 3.00], p = 0.03) and serum LDH levels >500 U/l (HR 3.62, 95% CI: [1.76; 7.44], p < 0.001). Clinical performance, symptom response and serum LDH stayed independently prognostic for survival in multivariate analysis. RT was well-tolerated and except for grade III myelosuppression in 19 cases (17.3%), no high-grade acute toxicities were observed. Neurologic symptom stabilization was achieved in 83 cases (75.5%) and a sizeable improvement in 39 cases (35.5%). Conclusion: Radiotherapy is a well-tolerated and efficacious means of providing symptom palliation for patients with LC, delaying neurologic deterioration while probably not directly influencing survival. Prognostic factors such as clinical performance, neurologic response and serum LDH can be used for patient stratification to facilitate treatment decisions.


[The Abbreviated Injury Scale (AIS). Options and problems in application].
The new AIS (Abbreviated Injury Scale) was released with an update by the AAAM (Association for the Advancement of Automotive Medicine) in 2008. It is a universal scoring system in the field of trauma applicable in clinic and research. In engineering it is used as a classification system for vehicle safety. The AIS can therefore be considered as an international, interdisciplinary and universal code of injury severity. This review focuses on a historical overview, potential applications and new coding options in the current version and also outlines the associated problems.


The relationship between packed cell volume and the course of disease in milk fever in dairy cows.
Results from a field investigation involving 1086 cows with clinical milk fever, revealed a clear relationship between PCV at the time of first treatment and the subsequent course of the disease. Average PCV was progressively higher as the cows required one, two, or more than two treatments before recovery, and was highest in cows which subsequently failed to recover. PCV in healthy, periparturient cows was considerably lower than in cows with milk fever. PCV was negatively correlated with plasma Ca, and varied, moreover, with the time of first treatment in relation to calving, and also with the length of time the cow had been recumbent before being treated for the first time. PCV was also measured during the further course of the disease in cows which received more than one treatment (2nd to 6th treatments).


[A particular hepatocellular carcinoma combining the ordinary and the fibrolamellar variant].
Fibrolamellar carcinoma (FLC) of the liver is a rare variant of hepatocellular carcinoma (HCC) occurring on non cirrhotic liver. Since its first description by Hugh Edmondson in 1956, 200 cases of FLC have been reported in the literature, but only some cases describe the association of the ordinary HCC with the FLC within the same lesion. We report in this study the case of a 14-year-old female patient with a hepatic mass whose radiological aspect evoked a nodular and focal hyperplasia. Histologically, this tumor was composed of area of FLC mixed with ordinary HCC. Staining for cytokeratine 7 was positive in the FL component and negative in the ordinary HCC component.


A luminescent metal-organic framework constructed using a tetraphenylethene-based ligand for sensing volatile organic compounds.
By using a tetraphenylethene (TPE)-based ligand, tetrakis[4-(4-carboxyphenyl)phenyl]ethene (H4TCPPE), a porous metal-organic framework [Zn2(TCPPE)] (1) is synthesized, which exhibits strong fluorescence and is capable of gas adsorption and sensing volatile organic compounds.


[Pneumopathy due to sulfasalazopyrine. A case with a challenge test].
The complications of treatment with sulfasalazopyrine(SSP) are rare. We report a case of a 68 year old patient who was hospitalised for a hectic fever with weight loss, chest pain and dyspnoea of effort. This patient had been treated for 2 1/2 months for a haemorrhagic proctocolitis with 3 gms. per day of SSP. There was a leucocytosis of 23 700/mm3 of which there were 3,318 eosinophils/mm3. The pulmonary radiograph showed a predominantly interstitial pattern at the apices in the axillary region and in the costo-phrenic angle. The broncho alveolar lavage (LBA) was normal. A thoracic scan confirmed the interstitial syndrome and the existence of pleural thickening in the upper part of the lungs. As drug induced pulmonary disease was suspected SSP was stopped. The patient became apyrexial in 48 hours without any further treatment. Thirty days later the pulmonary radiograph and the laboratory investigations had returned to 'normal and a challenge test using the drug was given whilst the patient was still in hospital. After 24 hours there was a febrile peak of 38.7 degrees C and 36 hours later there was a leucocytosis once more of 19 700/mm3 of which there were 1,100 eosinophils/mm3. The pulmonary radiograph showed diffuse bilateral interstitial opacities. The treatment was stopped and the fever disappeared within 24 hours. After a review of the literature, two points of this case were discussed in particular: the frequency of pulmonary disease occurring as a complication of SSP and the indication for challenge test.


California sea lion (Zalophus californianus) lymph-node explant reveals involvement and possible transcriptional regulation of SLAM and nectin-4 during phocine distemper virus infection.
Phocine distemper virus (PDV) is a significant cause of mortality for phocid seals; however, the susceptibility of otariids to this virus is poorly understood. The authors used a lymph-node explant culture system from California sea lions (Zalophus californianus, CSL) to investigate: (1) the role of signaling lymphocyte activation molecule (SLAM) and nectin-4 in PDV infection and their cellular expression patterns, (2) if PDV induces transcriptional regulation of cell-entry receptors, and (3) the involvement of apoptosis in PDV infection. PDV replicated in the lymph-node explants with peak replication 3 days post-infection (dpi), but the replication was not sustained 4 to 5 dpi. The PDV+ cells co-localized SLAM and nectin-4. These cells expressed IBA1, indicating a histiocytic lineage. Comparison of receptor expression between infected and mock-infected lymph nodes suggested transcriptional downregulation of both receptors during the initial stage of infection and upregulation during the late stage of infection, but the values lack of statistical significance. Cleaved caspase-3+ cells were slightly increased in the infected lymph nodes compared with the mock-infected lymph node from 1 to 4 dpi, but without statistical significance, and a few apoptotic cells co-expressed PDV. The results suggest that lymph-node explants might be an important model to study PDV pathogenesis. CSLs have the potential to be infected with PDV, as they express both cell-entry receptors in histiocytes. The lack of statistical significance in the PDV replication, transcriptional regulation of viral receptors, and changes in apoptosis suggest that although CSL might be infected by PDV, they might be less susceptible than phocid species.


Comparison of international medical graduates with US medical students and residents after a four-week course in palliative medicine: a pilot study.
The need for doctors who have skills in pain management and palliative medicine is greatest in low and moderate resource countries where patients most frequently present to their health care system with advanced illness and greater than 80% of the global deaths occur. While medical students trained in the United States are required to have training in palliative medicine, international medical graduates (IMGs), who have completed medical school outside North America, may not have the same exposure to palliative medicine training as U.S. physicians. The goal of this study was to evaluate whether a four-week course in palliative medicine could bring IMG attitudes, concerns, competence, and knowledge to the level of U.S. trainees. As part of a prospective cohort study, 21 IMGs from 14 countries participated in a four-week course in palliative medicine. Attitudes, concerns, self-reported competence, and knowledge were assessed pre-course and post-course. The course was evaluated weekly and at the end of the four-week program. The data from the IMGs was compared to data from U.S. medical students and residents using the same assessment tools. After the course, IMGs had significantly decreased concern about ethical and legal issues in palliative medicine to the level of U.S.-trained residents and a significant increase in knowledge and self-rated competence equivalent to the level of U.S. trainees. A four-week course in palliative medicine can improve the levels of concern, knowledge and self-assessed competence in IMGs to the level of US trainees.


Supplementation with zinc between meals has no effect on subsequent iron absorption or on iron status of Chilean women.
Studies on the effect of zinc (Zn) supplementation on iron absorption and iron status have shown mixed results. We investigated the effect of daily supplementation with 20 mg of Zn for a period of 2 mo on iron absorption and iron status of Chilean women. Forty-four non-anemic, clinically healthy women 35 to 45 y of age were randomly selected to receive daily 20 mg of Zn, as Zn sulfate, or a placebo between meals for a period of 2 mo. Iron and zinc biochemical indicators and iron absorption studies were assessed at baseline and at the end of the study. Iron absorption was measured using the double radioisotopic technique. The geometric mean (range +/- 1 standard deviation) absorption of iron before supplementation between the Zn-supplemented and placebo groups was similar (31.2, 11.2 +/- 86.3, versus 27.4, 14.4 +/- 52.2, respectively, P = 0.97). Absorption increased significantly after the 2-mo supplementation period (P = 0.049), but there were no group-wise differences at the end of the trial (34.4, 17.5 +/- 67.3, versus 39.8, 20.9 +/- 75.8, respectively, P = 0.97). The geometric mean plasma Zn concentrations did not change significantly in either group during the course of the study (P = 0.47). There was no significant effect of Zn supplementation on any of the iron indicators studied. Supplementation of 20 mg of Zn between meals for a period of 2 mo had no effect on subsequent iron absorption or iron status of Chilean women.


Future technologies.
Research and development in the area of body composition has undergone considerable changes in the last decade. These changes have resulted in part from the improvement of established techniques-but also from the introduction of methods based upon principles new to body composition studies. One can observe in recent developments a trend towards less invasive techniques, and cheaper, more portable instrumentation. There has also been a move towards improving the efficacy of the information obtained. The trend towards less invasive techniques, which includes lower dose, is particularly important when considering applications involving children. The question of 'future technologies' needs to be considered against the background of these developments if one is to propose the direction of future research. This paper considers possible new and modified technologies which may find application in the measurement of body composition. In addition, currently emerging technologies which need further research and development will be discussed. Examples of technologies examined in this paper include: •a possible new approach to measurement of bone mineral density in neonates using laser beam transmission, •possible modification of dual-energy X-ray absorption (DEXA) techniques for improved precision in the measurement of the relative lean/fat component, and •the research required to validate the use of multifrequency bio-electrical impedance analysis for measurement of extracellular and total body water.


Morphometry of right and left ventricular myocardium after strenuous exercise in preconditioned rats.
Young male rats were exposed to a biphasic training program in which a 7-week preconditioning period of moderate treadmill exercise was followed by 8 weeks of strenuous endurance running. In comparison with sedentary control animals, the trained rats at 20 weeks of age had developed myocardial hypertrophy of the right ventricle (20%) and interventricular septum (23%), but there was no difference in the weight of the left ventricular free wall. Myocyte hypertrophy (26%) in the right ventricle was achieved through an increase in mean cell length (24%) and the addition of new sarcomere units in series. Exercise induced no acceleration of capillary growth in either ventricle, leading to significant decreases in the capillary luminal volume density (-21%) and surface density (-16%) in the right ventricle. Such alterations in the structural properties of the microvasculature implicated in oxygen availability and diffusion suggest that vigorous exercise, even after a preconditioning period, may still be detrimental to the myocardium. The techniques of myocardial morphometry were examined with respect to potential errors associated with oblique tissue sections and the use of light versus electron microscopy for cell counting. It was shown that the practical effects of obliquity are negligible and that electron microscopic resolution is essential.


Comparison of 5% Sulfur Hexafluoride Versus 100% Air Tamponade in Descemet Membrane Endothelial Keratoplasty.
To compare the rebubbling rate and clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) with 5% sulfur hexafluoride (SF6) gas versus 100% air as a tamponade for graft attachment. Retrospective, comparative, interventional case series including 368 consecutive pseudophakic eyes with Fuchs endothelial dystrophy or pseudophakic bullous keratopathy that underwent DMEK in a tertiary referral center between October 2010 and August 2015 using either air (group 1, 191 eyes) or 5% SF6 (group 2, 177 eyes) as a tamponade. The rebubbling rate, complications, best-corrected distance visual acuity (BCVA), manifest refraction, and endothelial cell density were analyzed before and at 1 week, 1, 3, 6, 12, 24, and 36 months after surgery. The rebubbling rate was 20.4% (39/191, group 1) versus 6.8% (12/177, group 2; P < 0.001). Complications included cystoid macular edema (n = 5, group 1, and n = 10, group 2; P = 0.14) and 1 case of presumed allograft rejection (n = 1, group 2). The follow-up period was 12 ± 8 months for group 1 and 6 ± 4 months for group 2. BCVA (logarithm of the minimum angle of resolution) had improved after 12 months from 1.43 ± 0.63 to 0.18 ± 0.26 (group 1, P < 0.001) and from 1.8 ± 0.63 to 0.18 ± 0.17 (group 2, P < 0.001). The percentage of eyes with BCVA ≥0.2 logarithm of the minimum angle of resolution at 12 months was 70.9% (90/127, group 1) and 78.4% (40/51, group 2; P = 0.3). Endothelial cell loss at 12 months after DMEK was 44 ± 18% (group 1) versus 33 ± 15% (group 2, P = 0.07). The use of a tamponade with 5% SF6 yielded a significantly lower incidence of graft detachment requiring surgical reintervention with no detrimental effect on graft endothelial cells. Thus, routine use of 5% SF6 for a graft tamponade in DMEK is recommended.


OXPHOS dysfunction regulates integrin-β1 modifications and enhances cell motility and migration.
Mitochondria are central organelles for cellular metabolism. In cancer cells, mitochondrial oxidative phosphorylation (OXPHOS) dysfunction has been shown to promote migration, invasion, metastization and apoptosis resistance. With the purpose of analysing the effects of OXPHOS dysfunction in cancer cells and the molecular players involved, we generated cybrid cell lines harbouring either wild-type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbour the pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)]. tRNAmut cybrids exhibited lower oxygen consumption and higher glucose consumption and lactate production than WT cybrids. tRNAmut cybrids displayed increased motility and migration capacities, which were associated with altered integrin-β1 N-glycosylation, in particular with higher levels of β-1,6-N-acetylglucosamine (GlcNAc) branched N-glycans. This integrin-β1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-β1 and also with increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate than WT cybrids, however, when injected in nude mice, tRNAmut cybrids produced larger tumours and showed higher metastatic potential than WT cybrids. We conclude that mtDNA-driven OXPHOS dysfunction correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer cell mitochondria and the extracellular matrix.


Protein synthesis by granulation tissue in bipedicle tube flaps.
The protein synthesis and the collagen synthesis by 2- to 7-week-old granulation tissue from implanted cylinders in bipedicle tube flaps on rabbits were measured in vitro by the incorporation of 14C-proline in proteins and in collagen hydroxyproline. Granulation tissue from cylinders implanted in skin folds were used as controls. In the skin flap group the protein synthesis was high at week 2, after which it decreased to week 5. In the controls the protein synthesis was the same as in the skin flap group at week 2. A decrease occurred between weeks 2 and 4 and a further decrease between weeks 6 and 7. At weeks 5 and 6 the protein synthesis was higher in the controls than in the skin flap group, but at week 7 it was the reverse. The collagen synthesis was high and equal in both groups at weeks 2 and 3 and then decreased to weeks 4 and 5. Between weeks 6 and 7 a further decrease was found in the controls, but not in the skin flap group.


Pattern of Head Injuries (Cranio-cerebral) due to Homicide in Association with Other Injuries: A Retrospective Post-mortem Study Autopsied at Dhaka Medical College Morgue House.
Annually, homicide contributes to a greater number of the total head injury cases. This retrospective study was conducted from 1(st) January 2009 to 31(st)December 2011 at Dhaka Medical College Mortuary. During this study period of three years a total of 15300 autopsies were done of which 5649 cases (36.84%) were of head injuries. Of them 747(13.22%) were of homicidal, 4080(72.22%) road-traffic accidents, 502(8.88%) accidental and 320(5.66%) cases of fall from heights. Three hundred ninety eight (398) urban cases (53.27%) out numbered 307 rural cases (41.09%) followed by 42 unknown cases (5.62%). Most cases belong to the younger age group i.e. 21-40 years (43.34%) with male preponderance 470(63.10%). Defense wounds were present in 281 cases (37.82%) out of the total 747 homicidal head injuries. There were 206(27.57%) upper limb, 176(23.56%) spinal, 139(18.60%) abdominal, 135(18.07%) thoracic, 58(7.76%) lower limb and 33(4.41%) pelvic injuries found as associated injury. There were 258(34.53%) fractures of occipital followed by 209(28.29%) parietal, 113(15.01%) frontal, 104(13.75%) temporal, 24(3.21%) ant. Cranial fossa, 23(3.07%) post. Cranial fossa and 16(2.08%) of middle cranial fossa fractures. Extradural haemorrhage was more i.e. 434 cases (58.43%) followed by subdural, combination of all, subarachnoid and intra-cerebral haemorrhages. Cases of concussion were more common i.e. 445(59.75%) than lacerated and combination of them. Blunt weapon tops the list of causative weapons i.e. 669(89.22%) than firearms 59(8.07%) and sharp pointed weapons 19(2.68%).


Advantages and limitations of common testing methods for antioxidants.
Owing to the importance of antioxidants in the protection of both natural and man-made materials, a large variety of testing methods have been proposed and applied. These include methods based on inhibited autoxidation studies, which are better followed by monitoring the kinetics of oxygen consumption or of the formation of hydroperoxides, the primary oxidation products. Analytical determination of secondary oxidation products (e.g. carbonyl compounds) has also been used. The majority of testing methods, however, do not involve substrate autoxidation. They are based on the competitive bleaching of a probe (e.g. ORAC assay, β-carotene, crocin bleaching assays, and luminol assay), on reaction with a different probe (e.g. spin-trapping and TOSC assay), or they are indirect methods based on the reduction of persistent radicals (e.g. galvinoxyl, DPPH and TEAC assays), or of inorganic oxidizing species (e.g. FRAP, CUPRAC and Folin-Ciocalteu assays). Yet other methods are specific for preventive antioxidants. The relevance, advantages, and limitations of these methods are critically discussed, with respect to their chemistry and the mechanisms of antioxidant activity. A variety of cell-based assays have also been proposed, to investigate the biological activity of antioxidants. Their importance and critical aspects are discussed, along with arguments for the selection of the appropriate testing methods according to the different needs.


Spontaneous closure of the hymen during pregnancy.
Imperforate hymen is a rare disorder that is usually discovered at the onset of menstruation. In the literature, secondary closure of the hymen has been reported in 2 cases, both of which occurred subsequent to surgical procedures that involved the hymen. We report an interesting case of the spontaneous formation of an imperforate hymen during pregnancy in the absence of previous surgical procedures. Electron microscopic findings indicate hymenal tissue reorganization.


Variations in achievement of evidence-based, high-impact quality indicators in general practice: An observational study.
There are widely recognised variations in the delivery and outcomes of healthcare but an incomplete understanding of their causes. There is a growing interest in using routinely collected 'big data' in the evaluation of healthcare. We developed a set of evidence-based 'high impact' quality indicators (QIs) for primary care and examined variations in achievement of these indicators using routinely collected data in the United Kingdom (UK). Cross-sectional analysis of routinely collected, electronic primary care data from a sample of general practices in West Yorkshire, UK (n = 89). The QIs covered aspects of care (including processes and intermediate clinical outcomes) in relation to diabetes, hypertension, atrial fibrillation, myocardial infarction, chronic kidney disease (CKD) and 'risky' prescribing combinations. Regression models explored the impact of practice and patient characteristics. Clustering within practice was accounted for by including a random intercept for practice. Median practice achievement of the QIs ranged from 43.2% (diabetes control) to 72.2% (blood pressure control in CKD). Considerable between-practice variation existed for all indicators: the difference between the highest and lowest performing practices was 26.3 percentage points for risky prescribing and 100 percentage points for anticoagulation in atrial fibrillation. Odds ratios associated with the random effects for practices emphasised this; there was a greater than ten-fold difference in the likelihood of achieving the hypertension indicator between the lowest and highest performing practices. Patient characteristics, in particular age, gender and comorbidity, were consistently but modestly associated with indicator achievement. Statistically significant practice characteristics were identified less frequently in adjusted models. Despite various policy and improvement initiatives, there are enduring inappropriate variations in the delivery of evidence-based care. Much of this variation is not explained by routinely collected patient or practice variables, and is likely to be attributable to differences in clinical and organisational behaviour.


Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice.
Fifty-nine transgenic mice from a lineage that overproduces the hepatitis B virus large envelope polypeptide and accumulates high intrahepatic concentrations of hepatitis B surface antigen were followed for evidence of liver disease throughout their 24-month life span. By 4 months of age all mice displayed biochemical and histological evidence of moderately severe chronic hepatitis which was followed sequentially by the development of regenerative nodules and oval cell hyperplasia (by 6 months), liver cell adenomas (by 8 months), and hepatocellular carcinomas (by 12 months of age). One hundred % of mice in this lineage developed hepatocellular carcinoma by 20 months of age, whereas no histopathological changes were observed in age- and sex-matched nontransgenic littermate controls over the same period of observation. These results indicate that overproduction of the hepatitis B virus large envelope polypeptide initiates a process characterized by liver cell injury, inflammation, and regenerative hyperplasia, which places large numbers of hepatocytes at risk for the development of transforming mutations, and inexorably progresses to hepatocellular carcinoma. We suggest that this is a general mechanism of hepatocarcinogenesis that may be operative in human hepatitis B virus infection and other necroinflammatory liver diseases as well.


Valvular heart disease and the use of dopamine agonists for Parkinson's disease.
Ergot-derived dopamine receptor agonists, often used in the treatment of Parkinson's disease, have been associated with an increased risk of valvular heart disease. We performed an echocardiographic prevalence study in 155 patients taking dopamine agonists for Parkinson's disease (pergolide, 64 patients; cabergoline, 49; and non-ergot-derived dopamine agonists, 42) and 90 control subjects. Valve regurgitation was assessed according to American Society of Echocardiography recommendations. The mitral-valve tenting area was also measured and used as a quantitative index for leaflet stiffening and apical displacement of leaflet coaptation. Clinically important regurgitation (moderate to severe, grade 3 to 4) in any valve was found with significantly greater frequency in patients taking pergolide (23.4%) or cabergoline (28.6%) but not in patients taking non-ergot-derived dopamine agonists (0%), as compared with control subjects (5.6%). The relative risk for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (P=0.008), 4.2 for aortic regurgitation (P=0.01), and 5.6 for tricuspid regurgitation (P=0.16); corresponding relative risks in the cabergoline group were 4.6 (P=0.09), 7.3 (P<0.001), and 5.5 (P=0.12). The mean mitral tenting area was significantly greater in ergot-treated patients and showed a linear relationship with the severity of mitral regurgitation. Patients treated with ergot derivatives who had grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than had patients with lower grades. The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists, as compared with control subjects. These findings should be considered in evaluating the risk-benefit ratio of treatment with ergot derivatives.


Well-being and morbid obesity in women: a controlled therapy evaluation.
Morbidly obese individuals are unlikely to reach and maintain normative weights. Thus, interventions aimed at alleviating corollary problems, independent of attempts at weight loss, are appropriate. A cognitive group treatment program (CT) was developed which incorporated a nondieting approach, regular exercise, and use of alternative coping skills. Weight loss per se was not a focus of the intervention. The purpose of the current work was to evaluate this program in a controlled, comparative treatment outcome study. Sixty-two obese women with a history of treatment failures were randomly assigned to the CT program, a behavior therapy weight loss program (BT), or a wait-list control group. For CT participants, depression, anxiety, and eating-related psychopathology decreased significantly over the course of treatment while perceptions of self-control increased; BT and control subjects showed no significant changes in these variables. Women in both active treatment groups lost significant amounts of weight, while members of the control group showed a nonsignificant increase in weight. At 6-month follow-up, treatment benefits were maintained. Findings suggest that interventions not directly aimed at weight loss can enhance psychological well-being and thus may be appropriate for some obese women.


Depression Symptoms, Acculturation, Needing Care, and Receiving Care: A Study of Adolescents Living in California.
The objectives of this study are 1) to depict the prevalence of moderate depressive symptoms (MDS) in adolescents living in California, 2) to examine the role of acculturation in reported MDS, and 3) to identify any relationship between acculturation, "needing emotional help," and "receiving psychological or emotional counseling," as reported by adolescents with MDS. We analyzed data from a cross-sectional population-based telephone survey for adolescents who completed the California Health Interview Survey (CHIS) in 2007, 2009, and 2011-2012. The primary predictor variable was level of acculturation. Outcome variables were 1) the presence of MDS, 2) whether participants needed help with emotional problems, and 3) whether they had received psychological or emotional counseling. Of the sample (n = 9816), 6.0% had MDS; 50% of these reported needing help for emotional problems, and 30% reported receiving psychological/emotional counseling. Multivariate analysis that included the interaction effects of race/ethnicity and acculturation showed that the latter was not associated with any of the outcome variables. However, Latino adolescent with MDS and moderate acculturation were less likely to report needing help for psychological/emotional problems, compared to their White counterparts with higher acculturation. Our findings suggest disparities in reporting depression symptoms and receiving psychological/emotional help are not driven by adolescents' acculturation levels. However, more studies are needed to clarify what cultural factors facilitate or inhibit moderately acculturated Latino adolescents from reporting needing help for psychological/emotional problems.


Localized outbreak of enteroviral meningitis in adults.
During a thorough surveillance of viral infections of the central nervous system an outbreak of aseptic meningitis was discovered in the western part of Finland in late 1985. The 21 diseased young adults were carefully studied by different virological methods. A presumed viral etiology, in all cases of enteroviral origin, was found in 16 of 20 (80%) with adequate specimens. Four different enteroviruses were associated with this episode; in 9 cases the presumed etiological agent was echovirus 5, while coxsackie B5, echo 25 and echo 17 viruses appeared to be responsible for 4, 2 and 1 case, respectively. Sensitivity of different diagnostic methods as regards detection of the echovirus 5 infections was in order: increase of type-specific neutralizing serum antibodies, isolation of virus from faeces, isolation from throat and group diagnosis by demonstrating an increase in complement-fixing antibodies to coxsackie B5 virus antigen.


Effect of hemodialysis on plasma glucose profile and plasma level of liraglutide in patients with type 2 diabetes mellitus and end-stage renal disease: a pilot study.
The effect of hemodialysis on the plasma glucose profile and liraglutide level after liraglutide injection was investigated in patients with diabetes and end-stage renal disease (ESRD). Either 0.6 mg or 0.9 mg liraglutide was subcutaneously administered daily to 10 Japanese type 2 diabetic patients with ESRD. Hemodialysis was conducted on days 1 and 3. Plasma liraglutide and glucose concentrations were measured by enzyme-linked immunosorbent assay and a continuous glucose monitoring system, respectively. The safety profile of liraglutide was also assessed. Hemodialysis had no effect on the pharmacokinetic parameters of liraglutide in patients with diabetes and ESRD; the maximum plasma concentration (Cmax), tmax, area under the concentration-time curve (AUC), and CL/f were unaltered. Similarly, hemodialysis did not affect the mean or minimum glucose levels, AUC, or duration of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) following liraglutide administration. However, significant increases in mean amplitude of glycemic excursions (MAGE) and standard deviation (SD) as markers of glucose fluctuation, and the maximum glucose level were observed during hemodialysis. No adverse events, including hypoglycemia, were observed after liraglutide injection, either off-hemodialysis (day 2) or on-hemodialysis (day 3). Liraglutide was well tolerated in patients with type 2 diabetes and ESRD undergoing hemodialysis. The present results suggested that hemodialysis did not affect the pharmacokinetic profile of liraglutide or most glycemic indices, with the exception of MAGE, SD, and the maximum glucose level. These results suggested that it may be possible to use liraglutide during hemodialysis for diabetes with ESRD, without dose adjustment. Trial Registration UMIN Clinical Trials Registry (UMIN-CTR) UMIN000010159.


The sixteen CB(11)H(n)Me(12-n)(-) anions with fivefold substitution symmetry: anodic oxidation and electronic structure.
The 15 symmetrically methylated derivatives of the CB11H12(-) anion (1a) have been synthesized and found to vary greatly in ease of oxidation. Cyclic voltammetry in liquid SO2 yielded fully reversible oxidation potentials for five of those that have no adjacent unsubstituted vertices in positions 7-12; three others showed some indication of reversibility. The anions 1a-16a and the Jahn-Teller distorted neutral radicals 1r-16r have been characterized by ab initio and density functional theory calculations. In the state average CASSCF(13,12)/6-31+G* approximation, the ground state potential energy surface of 1r contains five symmetry-related pairs of minima. The computational results account for the reversible redox potentials very well when the solvent is included explicitly (RI-DFT(BP)/TZVP, COSMO). For display and for a semiquantitative understanding of methyl substituent effects in terms of perturbation theory, the molecular orbitals of 1a have been expressed in the symmetry-adapted cluster basis. The results serve as an underpinning for a set of additive empirical increments for redox potential prediction. Relative to the usual hydrogen standard, a single methyl group facilitates oxidation by approximately 50, 70, 70, and 10 mV in positions 1, 2, 7, and 12, respectively. This electron donor effect on the redox potential is due to a contribution, whereas those of (inductive and direct field) type are negligible.


Escalating therapy of cutaneous side effects of EGFR inhibitors: experience of German reference centers.
Recommendations for the management of cutaneous adverse effects of inhibitors of the epidermal growth factor receptor (EGFR) are urgently needed. In this context an expert panel of German dermatologists recently proposed a 3-step management concept based on personal experience and a current literature consensus. While steps 1 and 2 addressed general and preventive measures, as well as the therapy that can be performed by the primary treating physician, here we address the management of challenging cases (step 3) that do not respond well to basic measures and should be referred to an experienced dermatologist.


Impact of Venoarterial Extracorporeal Membrane Oxygenation Flow on Outcomes in Cardiogenic Shock.
Venoarterial extracorporeal membrane oxygenation (VA ECMO) is used to provide cardiopulmonary support in cardiogenic shock; however, high extracorporeal flow may increase left ventricular (LV) afterload leading to LV distention and intracardiac stasis. It is unclear how ECMO flow affects patient outcomes and complications related to ECMO. Retrospective review of patients at a single institution placed on VA ECMO from 2007 to 2018 was performed. Patients were divided into full flow (flow index > 2.2 L/min/m2) and partial flow (flow index < 2.2 L/min/m2) groups. In-hospital mortality and markers of end-organ perfusion were compared between groups balanced for risk factors using propensity score inverse probability of treatment weighting. ECMO-related complications such as LV distention, limb ischemia, and bleeding were recorded. There were 488 patients included, 405 (83%) in the partial flow group, and 83 (17%) in the full flow group. No major differences in age, gender, or comorbidities were found. There was no difference in in-hospital mortality between groups (51% vs. 55%, p = 0.59). At 72 hours post-ECMO initiation, there was no difference in the change in renal, hepatic function, or lactate from baseline nor in the rates of continuous venoveno hemofiltration initiation (p = 0.41). There was a trend towards the decreased incidence of LV distention requiring LV vent placement in the partial flow group (12% vs. 7%, p = 0.16). Compared with full flow VA ECMO, partial flow VA ECMO in carefully selected patients results in similar in-hospital mortality and provides similar end-organ perfusion for the treatment of refractory cardiogenic shock.


Causation and cleanliness: George Callender, wounds, and the debates over Listerism.
This article reexamines the surgical and historiographic debate over antisepsis and the germ theory through the work of the prominent London surgeon George W. Callender (1830-1879) and the statistical records of St. Bartholomew's Hospital. Surgeons in the mid-nineteenth century faced a rising incidence of wound infection and its systemic complications. Examining mortality and complication rates by type of wound, however, suggests that the extent of this crisis is often overstated. Callender himself occupied a frequently overlooked middle ground in the debate over Listerism. On the one hand, his program of cleanliness, which antedated Lister's work and extended from the wound to the ward, produced excellent and influential results. On the other, while he was never an explicit critic of the germ theory, his writings demonstrate why Lister's collapse of causation into a single etiologic agent was so difficult for surgeons to accept.


Emergent Resistance to Dolutegravir Among INSTI-Naïve Patients on First-line or Second-line Antiretroviral Therapy: A Review of Published Cases.
None of the licensing studies of dolutegravir (DTG) reported any treatment-emergent resistance among DTG-treated individuals, though virological failure in treatment-naïve and treatment-experienced, integrase strand transfer inhibitor (INSTI)-naïve individuals has been reported in clinical practice. While the spectrum of dolutegravir-selected mutations and their effects on clinical outcome have been described, the clinical characteristics of these rare but important virological failure cases are often overlooked. In this perspective piece, we focus on key clinical aspects of emergent resistance to DTG among treatment-naïve and treatment-experienced INSTI-naïve patients, with an aim to inform clinical decision-making. Poor adherence and HIV disease factors contribute to emergent drug resistance, even in regimens with high resistance barriers. Patients with severe immunosuppression or poor adherence are under-represented in licensing studies, and these patients may be at higher risk of treatment failure with DTG resistance, which requires close clinical and laboratory follow-up.


Distinct mechanisms of integrin binding by Yersinia pseudotuberculosis adhesins determine the phagocytic response of host macrophages.
The enteropathogenic yersiniae express two outer membrane adhesins, invasin and YadA, that contribute to pathogenesis. While invasin binds directly to beta1 integrin receptors with high affinity, YadA binds indirectly through extracellular matrix (ECM) components. In this study, Yersinia pseudotuberculosis inv and yadA mutants were used to investigate how these distinct binding mechanisms compare and potentially compete in activating signalling pathways and promoting bacterial uptake by host macrophages. The efficiency of adhesin-mediated phagocytic responses was found to be dependent on the relative expression of invasin and YadA on the bacterial surface as well as the expression of ECM proteins in the extracellular milieu. Under conditions of low concentrations of ECM, invasin was found to be the dominant adhesin, promoting high levels of phagocytosis coincident with robust and sustained activation of the protein tyrosine kinases Fak and Pyk2, phosphorylation of the adaptor molecule Cas and activation of the small GTPase Rac1. In the presence of higher concentrations of ECM, YadA became the dominant functional adhesin through its ability to engage integrin receptors via an ECM bridge. We propose a model whereby invasin promotes robust and prolonged activation of phagocytic signalling cascades by inducing a 'high-affinity' integrin conformation as well as integrin clustering. We postulate that YadA-ECM promotes phagocytosis through a more transient activation of signalling cascades that arises from integrin clustering in the context of a cross-linked fibrillar ECM network.


Irregular Cellular Learning Automata.
Cellular learning automaton (CLA) is a recently introduced model that combines cellular automaton (CA) and learning automaton (LA). The basic idea of CLA is to use LA to adjust the state transition probability of stochastic CA. This model has been used to solve problems in areas such as channel assignment in cellular networks, call admission control, image processing, and very large scale integration placement. In this paper, an extension of CLA called irregular CLA (ICLA) is introduced. This extension is obtained by removing the structure regularity assumption in CLA. Irregularity in the structure of ICLA is needed in some applications, such as computer networks, web mining, and grid computing. The concept of expediency has been introduced for ICLA and then, conditions under which an ICLA becomes expedient are analytically found.


Stent-grafts improve secondary patency of failing hemodialysis grafts.
Failing hemodialysis grafts continue to pose a challenge in the care of patients with end-stage renal disease (ESRD). We review our experience using percutaneous stent-grafts for the treatment of venous outflow stenosis and occlusion in order to assess their efficacy in nonautologous graft salvage. This is a retrospective review of patients treated with percutaneous Viabahn® stent-grafts for failing hemodialysis arteriovenous grafts (AVGs), between 6/2006 and 12/2009. All stent-grafts were deployed across the venous anastomosis to address the outflow obstruction. Patency and re-intervention rates were estimated using Kaplan-Meier analysis. Twenty patients had stent-grafts placed. Successful stent-grafting was defined as <30% residual stenosis and the ability to dialyze through the graft post-treatment. Technical success for stent-grafting was 100%. Median follow-up was 23 months (range 3 to 37 months). Stent-graft patency at 6 months: 94.7%, 12 months: 94.7%, 18 months: 82.1%, 24 months: 82.1%, 36 months: 82.1%. Freedom from re-intervention was 69% at 24 months and 50% at 36 months. Two AVGs failed and had to be removed without further interventions, because of complete occlusion and infection. Two patients (10%) required re-intervention for arterial inflow stenosis. One patient (5%) required balloon angioplasty and stenting of stenosis distal to the stent-graft. One patient (5%) developed in-stent stenosis and was treated with placement of a new stent. Graft salvage rate was 80% at 36 months. Stent-grafts can be successfully used to improve freedom from re-intervention rates and overall patency rates of failing AVGs.


Insight into Tetrabromobisphenol A-Associated Liver Transcriptional Landscape via Single Cell RNA Sequencing.
In recent years, there has been growing concern over the rising incidence of liver diseases, with increasing exposure to environmental toxins as a significant contributing factor. However, the mechanisms of liver injury induced by environmental pollutants are largely unclear. Here, using tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, as an example, environmental toxin-induced liver toxicity in mice is characterized via single-cell sequencing technology. Heterogeneous gene expression profiles after exposure to TBBPA in major cell types of the liver are demonstrated. In hepatocytes, pathway analysis of differentially expressed genes reveals the enhanced interferon response and diminished metabolic processes. The disrupted endothelial functions in TBBPA-treated cells are then shown. Moreover, the activation of M2-polarization in Kupffer cells, as well as activated effector T and B cells are unveiled in TBBPA-treated cells. Finally, ligand-receptor pair analysis shows that TBBPA disrupts cell-cell communication and induces an inflammatory microenvironment. Overall, the results reveal that TBBPA-induced dysfunction of hepatocytes and endothelial cells may then activate and recruit other immune cells such as Kuffer cells, and T/NK cells into the liver, further increasing inflammatory response and liver injury. Thus, the results provide novel insight into undesiring environmental pollutant-induced liver injury.


Partial anomalous pulmonary venous return.
Partial anomalous pulmonary venous return (PAPVR) is an uncommon congenital abnormality that occurs in 0.4 to 0.7% of postmortem examinations. Ninety percent of these anomalies are associated with an atrial septal defect. Partial anomalous pulmonary venous return occurs more commonly on the right than the left and is manifested by abnormal return of the pulmonary veins to the central venous circulation. Most patients are asymptomatic, but when symptoms are present they are due to shunting of oxygenated blood to the venous circulation. We submit the case of a recently activated solider who presented with dyspnea on exertion refractory to inhaled corticosteroids and an 8.5-mm solitary pulmonary nodule. Further diagnostic imaging revealed PAPVR. Our case appears to be the first report of a solitary pulmonary nodule as the initial presentation of a right upper lobe PAPVR with return to the superior vena cava in the absence of associated atrial septal defect.