Keratin biosynthesis in normal mouse epithelia and in squamous cell carcinomas. mRNA-dependent alterations of the primary structure of distinct keratin subunits in tumors.
The keratin polypeptide patterns of two murine transplantable squamous cell carcinomas--originally induced by chemical means in the back skin and in the forestomach epithelium--are deficient in high molecular weight keratin subunits (greater than 60 kDa) invariably present in the corresponding normal tissues. In addition, the keratin polypeptide composition within the low molecular weight range showed further alterations with regard to the corresponding keratin subset of normal tissues in that both tumors expressed a 40-kDa protein, and a 56-kDa protein was selectively found in the forestomach tumor. A comparison of the charge properties of normal and tumor keratin polypeptides revealed that the two uppermost tumor proteins at 60 and 58 kDa were basic in nature whereas their normal molecular weight counterparts belonged to the acidic subset of the pattern. These tumor proteins also showed mutually identical peptide maps which, however, were considerably different from those of the normal proteins. The remaining tumor keratin subunits at 52, 50, 48, and 45 kDa, common also to the normal tissues, had retained their normal charge properties. In vitro translation of mRNA, isolated from both normal and tumor tissue, revealed that every tumor keratin polypeptide is encoded by its own mRNA. In contrast to normal keratinizing tissues, there is therefore no indication of post-translational protein processing in tumors. The in vitro translation products of tumor RNAs had all properties in common with the in vivo tumor proteins, thus indicating that every deviation of the tumor keratin spectrum from the normal state is determined at the mRNA level.


Prevalence of inflammatory bowel disease amongst Mormons in Britain and Ireland.
The prevalence of Crohn's disease (79/10(5)), ulcerative colitis (389/10(5)) and appendicectomy (2751/10(5)) were measured in a survey of the Mormon church in Britain and Ireland. Details were obtained from 230 of the 342 branches in Britain which had a membership of 56,000 people although only 17,700 people were active members. The prevalence of Crohn's disease was comparable to that reported from various centres in Britain, but ulcerative colitis was significantly commoner amongst Mormons while the frequency of appendicectomy was significantly reduced.


The effects and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis: a meta-analysis and systematic review.
It is necessary to systematically evaluate the efficacy and adverse reactions of pirfenidone in the treatment of patients with idiopathic pulmonary fibrosis (IPF). Pubmed et al. databases were searched up to March 15, 2021 for randomized controlled trials (RCT) of pirfenidone in the treatment of IPF. Two authors collected and compared the indicators including progression-free survival (PFS), vital capacity (VC), forced vital capacity (FVC), and adverse reactions. RevMan 5.3 software and Stata 15.0 software were used for meta-analysis. A total of 8 reports with 9 RCTs involving 1824 IPF patients were included. Meta-analysis results showed that compared with the control group, pirfenidone could prolong the PFS phase of IPF patients (HR = 0.65, 95% CI 0.55 ~ 0.76, P < 0.001), slow down the VC of IPF patients (SMD = 0.43, 95% CI 0.21 ~ 0.66, P < 0.001), and decrease FVC (SMD = 0.31, 95% CI 0.14 ~ 0.48, P < 0.001). The main adverse reactions of pirfenidone were gastrointestinal reactions, photosensitivity and skin rashes. Pirfenidone is beneficial to prolong the PFS of IPF patients, improve lung function, and it is safe for clinical use. However, more high-quality RCTs are still needed to provide reliable evidence for the treatment of IPF.


Paraventricular neurons control hamster photoperiodism by a predominantly uncrossed descending pathway.
Exposure of Syrian hamsters (Mesocricetus auratus) to short daylengths triggers testicular regression through a pathway involving hypothalamic regulation of sympathetic control over melatonin production in the pineal gland. Destruction of the hypothalamic paraventricular nucleus (PVN) blocks this response. In order to determine whether descending paraventricular influences are crossed or uncrossed, we removed the superior cervical ganglion unilaterally and destroyed the PVN on the same or opposite side. Ipsilateral PVN lesions were consistent with gonadal regression and high nocturnal pineal melatonin levels, while contralateral lesions blocked regression and significantly reduced the melatonin content of the gland. In order to determine whether PVN cell bodies are critical to the photoperiodic response, we produced axon-sparing lesions by injection of ibotenic acid. Lesions which produced cell loss as verified by both Nissl staining and immunocytochemistry blocked gonadal regression in hamsters exposed to short days. These findings indicate that PVN cells regulate pineal function, and hence gonadal regression, by a predominantly uncrossed pathway.


General dental practitioners' beliefs on the perceived effects of and their preferences for remuneration mechanisms.
To identify GDPs preferences for differing remuneration mechanisms and their beliefs on the effect of the mechanisms in care provision. Postal questionnaire survey of 300 GDPs holding an NHS contract with a London Health Authority. GDPs perceive that remuneration mechanisms are important in determining the provision of care but not overall disease levels. There were differences in the preferred remuneration mechanisms when working under the NHS compared with the non-NHS sector. When providing care under the NHS, either the current remuneration system or a salaried plus bonus would be the preferred choice, while for non-NHS care a fee-per-item mechanism is preferred. Fee-per-item arrangement was the preferred choice of younger general practitioners compared with older practitioners. Females showed a greater preference for a salaried with bonus arrangement compared with males. If policy makers are to use remuneration mechanisms to influence the provision of care effectively, the beliefs that care providers hold about various mechanisms are important to understand how they would respond to changes in the system.


EM autoradiographic study of the projections from the dorsal nucleus of the lateral lemniscus: a possible source of inhibitory inputs to the inferior colliculus.
The fine structure of the projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the inferior colliculus is examined in the cat. Anterograde axonal transport of 3H-leucine and EM autoradiographic techniques are used to label axonal endings from DNLL. The primary finding is that axonal endings from DNLL contain pleomorphic synaptic vesicles and make symmetrical synaptic contacts. This morphology is associated with inhibitory synapses. The projection from DNLL is the source of approximately one-third of the axonal endings with pleomorphic vesicles in the central nucleus of the inferior colliculus. In the contralateral central nucleus, only labeled endings with pleomorphic vesicles are found. By comparison, on the ipsilateral side, both endings with pleomorphic vesicles and, to a lesser degree, endings with round vesicles are labeled. Endings from DNLL are more numerous per unit area on the contralateral side. About half of the labeled axonal endings from DNLL terminate upon small dendrites, and another third terminate upon more proximal dendrites and several types of cell bodies. Many axonal endings form multiple synaptic contacts, sometimes on more than one postsynaptic structure. Sites of termination for axonal endings include dendritic spines and branch points of dendrites. These data support the hypothesis that the DNLL pathway to the inferior colliculus may have an inhibitory function. Previous studies show that DNLL neurons exhibit immunoreactivity to GAD and GABA antibodies. The crossed projection of DNLL to the inferior colliculus forms tonotopically organized bands that terminate as endings with pleomorphic vesicles. These endings may supply GABAergic inputs to the inferior colliculus. Thus, bands from DNLL could provide inhibitory inputs and overlap with bands from other sources that provide excitatory inputs. Overlapping bands may form unique synaptic domains in the inferior colliculus. The uncrossed projections from DNLL may provide the inferior colliculus with a more diffusely organized projection that could include excitatory and inhibitory inputs. Since the DNLL on one side may inhibit the opposite DNLL and the inferior colliculus, the DNLL pathway may regulate ascending inhibition to the midbrain. Presumed inhibitory inputs from DNLL to the inferior colliculus could be involved in binaural information processing and contralateral dominance.


Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke.
Ischemic stroke produces significant morbidity and mortality, and acute interventions are limited by short therapeutic windows. Novel approaches to neuroprotection and neurorepair are necessary. HuR is an RNA-binding protein (RBP) which modulates RNA stability and translational efficiency of genes linked to ischemic stroke injury. Using a transgenic (Tg) mouse model, we examined the impact of ectopic HuR expression in astrocytes on acute injury evolution after transient middle cerebral artery occlusion (tMCAO). HuR transgene expression was detected in astrocytes in perilesional regions and contralaterally. HuR Tg mice did not improve neurologically 72h after injury, whereas littermate controls did. In Tg mice, increased cerebral vascular permeability and edema were observed. Infarct volume was not affected by the presence of the transgene. Ectopic expression of HuR in astrocytes worsens outcome after transient ischemic stroke in mice in part by increasing vasogenic cerebral edema. These findings suggest that HuR could be a therapeutic target in cerebral ischemia/reperfusion.


Some observations of 31 spinal cord injury patients on whom the Bricker procedure was performed.
Only one-half of 31 spinal cord injury patients had good to fair results following cutaneous uretero-ileostomy. Poor results and deaths with urinary complications were more prevalent in the cervical and upper thoracic than in the more caudad cord lesions. There was a spread of 1/2 to 19 years in time interval from onset of spinal cord injury to performance of the Bricker procedure. A tendency for unsatisfactory postoperative courses was more associated with the longer time intervals.


Are plasma proteins a valid alternative for assessing nephrotic syndrome in children from low-income countries?
A diagnosis of nephrotic syndrome (NS) in children with edema relies on urinary albumin excretion and usually plasma protein (Pprot) and albumin (Palb) concentrations. In order to fit laboratory tests to optimal healthcare in low-resource countries, we established correlations between Pprot and Palb in children with NS (217 measurements in 60 patients) and in children with exudative enteropathy and chronic hepatopathy/liver insufficiency (186 measurements in 21 patients); all patients had repeated measurements at various stages of their disease. There was a good correlation between Pprot and Palb in children with idiopathic NS and genetic NS (ICC=0.8, p < 0.0001, 95% CI: 0.8-0.9 and ICC=0.8, p < 0.0001, 95% CI: 0.7-0.8, respectively), whereas the correlation was average (exudative enteropathy) or absent (chronic hepatopathy) in those without renal protein loss. Since Palb measurement is around two times more expensive than Pprot measurement, these results suggest giving priority to total Pprot measurement in the diagnosis and follow-up of children with the NS, mainly in low-resource countries.


The neighborhood food environment: sources of historical data on retail food stores.
With the rapidly increasing prevalence of obesity in the United States, and the minimal success of education-based interventions, there is growing interest in understanding the role of the neighborhood food environment in determining dietary behavior. This study, as part of a larger study, identifies historical data on retail food stores, evaluates strengths and limitations of the data for research, and assesses the comparability of historical retail food store data from a government and a commercial source. Five government and commercial listings of retail food stores were identified. The California State Board of Equalization (SBOE) database was selected and then compared to telephone business directory listings. The Spearman's correlation coefficient was used to assess the congruency of food store counts per census tract between the SBOE and telephone business directory databases. The setting was four cities in Northern California, 1979-1990. The SBOE and telephone business directory databases listed 127 and 351 retail food stores, respectively. The SBOE listed 36 stores not listed by the telephone business directories, while the telephone business directories listed 260 stores not listed by the SBOE. Spearman's correlation coefficients between estimates of stores per census tract made from the SBOE listings and those made from the telephone business directory listings were approximately 0.5 (p < .0001) for the types of stores studied (chain supermarkets, small grocery stores, and chain convenience markets). We conclude that, depending on the specific aims of the study, caution and considerable effort must be exercised in using and applying historical data on retail food stores.


Unintentional injury mortality among children under age five in urban and rural areas in the Sichuan province of west China, 2009-2017.
This study analysed trends in the unintentional injuries specific mortality rates among children under age five (UI-specific U5MRs) in urban and rural areas in the Sichuan province of western China. Data were obtained from the National Health Statistics Survey System. The Cochran-Armitage trend test was used to analyse the trends in UI-specific U5MRs and the proportion of unintentional injury deaths to total deaths. The Poisson regression model was used to compare the UI-specific U5MRs between rural and urban areas. The overall UI-specific U5MRs decreased from 3.8 to 1.7 per 1,000 live births from 2009 to 2017, with an average annual decline in the rates of 8.78% and 10.05% in urban and rural areas, respectively. The UI risk of death in rural areas was approximately 1.95 times that in urban areas (95% CI: 1.73-2.18; p < 0.01). A total of 49.9% of all the children in the study did not receive any treatment before death caused by UI. The UI-specific U5MRs significantly declined in Sichuan province from 2009 to 2017, but large disparities in UI-specific U5MRs in urban and rural areas still exist. Reducing the U5MRs due to UI should be a major public health concern in western China.


Suicide mortality in patients on lithium maintenance therapy.
Mood disorders are frequently recurrent and it has been shown that maintenance treatment can reduce long-term morbidity in this condition. It has also been shown that mood disorders carry an increased risk of suicide and that a significant proportion of individuals who commit suicide suffer from a mood disorder. This paper reports the results of a long term follow-up of a cohort of patients attending a specialist mood disorder clinic over a period of 18 years. Sixty-seven suffered from unipolar depression and 36 had bipolar or schizo-affective disorders In order to qualify for entry to the cohort the unipolar patients had to have had at least three episodes of depression and those with bipolar disorders had to have had at least three episodes - with at least one manic episode and one depressive episode. All patients were treated with lithium. The initial treatment refusal rate and drop our rates were low. The mortality from suicide in this group was compared with that reported in five recent studies - all of which involved patients who had not been given maintenance therapy. The standardised mortality ratio (SMR) for all causes for the whole group was 0.93. There were two suicides. In one case the patient had continued treatment with lithium until death and in the other the patient had discontinued treatment 12 months before death. The overall suicide rate was 1.3 per 1000 patient years. Amongst similar groups of patients who had not been given maintenance therapy suicide rates of about 5.5 per 1000 patient years have been reported. It is concluded that maintenance treatment of mood disorders reduces the suicide rate in this vulnerable group of patients.


A 5-year-old boy with acute neurological disorder from anteflexion-induced cervical cord compression after tracheal surgery: Radiological findings similar to Hirayama disease.
Constant neck flexion has been considered crucial to reducing anastomotic tension after tracheal resection. However, in rare cases, anteflexion can cause cervical cord damage, leading to acute neurological disorders such as tetraplegia. Here, we report a case of 5-year-old boy presenting with acute neurological disorder triggered by a chin-to-chest position over 4 days of deep sedation after cricotracheal resection. The radiological findings would suggest a mechanism similar to Hirayama disease, in which a shift of the dura leads to chronic muscular weakness and atrophy in young populations.


Automatic external defibrillator: key link in the chain of survival.
Sudden cardiac death is a major health problem. Worldwide success of resuscitation from out-of-hospital cardiac arrest is modest, with 5% to 10% survival to hospital discharge. In the chain of survival, early defibrillation (goal <5 min after collapse) is a major determinant of successful outcome of resuscitation. This goal is rarely achieved, but the automatic external defibrillator (AED) is a promising tool for lay defibrillation. The AED is a safe and effective device with nearly 100% accurate detection of ventricular fibrillation and nearly 100% accurate detection of a nonshockable rhythm. A large uncontrolled experience suggests improved outcome in nontraditional responders such as police. Controlled studies of community application of the AED are under way. The AED is a promising tool in the fight against sudden cardiac death and should be studied and supported by all scientists involved, including electrophysiologists.


Investigation of tolerance to chronic intrathecal morphine infusion in the rat.
Rats received chronic subcutaneous or intrathecal infusions of either saline or 25 micrograms/microliter/hr or 50 micrograms/microliter/hr of morphine sulfate. During five days of infusion individual groups of rats were assessed on either the nociceptive tail flick or hot plate test. After the infusions, the analgesic effects of either subcutaneous or intrathecal morphine test doses were evaluated. Tolerance developed to the analgesic effect of both subcutaneous and intrathecal morphine infusions on the tail flick test. Subcutaneously infused rats were also tolerant to a subcutaneous morphine challenge on this test. However, intrathecally infused rats were not tolerant to either the subcutaneous or intrathecal challenge. In contrast to these results, rats tested on the hot plate were not analgesic in response to either subcutaneous or intrathecal morphine infusions. However, these rats were tolerant when challenged with either subcutaneous or intrathecal morphine. The results are discussed in terms of the relative contribution of spinal and supraspinal sites to opiate tolerance, and the possibility that tolerance does not develop to the antinociceptive effect of spinal morphine on spinally mediated reflexes.


Modeling the SARS-CoV-2 Omicron variant dynamics in the United States with booster dose vaccination and waning immunity.
We carried out a theoretical and numerical analysis for an epidemic model to analyze the dynamics of the SARS-CoV-2 Omicron variant and the impact of vaccination campaigns in the United States. The model proposed here includes asymptomatic and hospitalized compartments, vaccination with booster doses, and the waning of natural and vaccine-acquired immunity. We also consider the influence of face mask usage and efficiency. We found that enhancing booster doses and using N95 face masks are associated with a reduction in the number of new infections, hospitalizations and deaths. We highly recommend the use of surgical face masks as well, if usage of N95 is not a possibility due to the price range. Our simulations show that there might be two upcoming Omicron waves (in mid-2022 and late 2022), caused by natural and acquired immunity waning with respect to time. The magnitude of these waves will be 53% and 25% lower than the peak in January 2022, respectively. Hence, we recommend continuing to use face masks to decrease the peak of the upcoming COVID-19 waves.


Selection of patients for laparoscopic pelvic lymphadenectomy prior to radical prostatectomy: a decision analysis.
Indications for laparoscopic pelvic lymphadenectomy prior to radical prostatectomy have not been established. Criteria to predict lymph node metastases were derived from the preoperative evaluations of 164 prostate cancer patients undergoing pelvic lymphadenectomy. Decision analysis was used to determine which criteria would be optimal indicators for laparoscopic pelvic lymphadenectomy prior to intended radical prostatectomy. Besides a digital rectal examination suggesting uncontained tumor, which was the best indication for laparoscopic pelvic lymphadenectomy, the most useful criteria were sonographic tumor volume > or = 3 cc and prostate-specific antigen (PSA) > or = 20 ng/mL. If either parameter was met, the sensitivity for identifying patients with pelvic lymph node metastases was 88 percent and the positive predictive value was 42 percent. When both were met, the sensitivity fell to 47 percent but the positive predictive value increased to 67 percent. A combination of Gleason biopsy score and PSA was the best criterion that was independent of transrectal ultrasonography. Using a PSA > or = 15 ng/mL for tumors with Gleason biopsy score > or = 7 or a PSA > or = 25 ng/mL for tumors with a Gleason biopsy score of 5-6 had a sensitivity of 71 percent and positive predictive value of 48 percent for identifying patients with pelvic lymph node metastases. In selecting patients for laparoscopic pelvic lymphadenectomy prior to radical retropubic prostatectomy, criteria with a positive predictive value greater than 39 percent maximize the utility of laparoscopic pelvic lymphadenectomy. Prior to radical perineal prostatectomy, laparoscopic pelvic lymphadenectomy will identify pelvic lymph node metastases that would otherwise be undetected by prostatectomy alone. The sensitivity of selection criteria, therefore, should be increased, as long as the positive predictive value remains above 20 percent.


HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence: a case report.
We report a case of incomplete HIV-1 suppression on a dolutegravir, lamivudine, and abacavir single-tablet regimen with the emergence of the H51Y and G118R integrase resistance mutations. Integrase sequencing was performed retrospectively by Sanger and next-generation sequencing. Rates of emergence and decline of resistance mutations were calculated using next-generation sequencing data. Dolutegravir plasma concentrations were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of H51Y and G118R on infectivity, fitness, and susceptibility to dolutegravir were quantified using cell-based assays. During periods of non-adherence to treatment, mutations were retrospectively documented only by next-generation sequencing. Misdiagnosis by Sanger sequencing was caused by the rapid decline of mutant strains within the retroviral population. This observation was also true for a M184V lamivudine-resistant reverse transcriptase mutation found in association with integrase mutations on single HIV genomes. Resistance rebound upon treatment re-initiation was swift (>8000 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, relative infectivity was 73%, 38%, and 43%; relative fitness was 100%, 35%, and 10% for H51Y, G118R, and H51Y+G118R viruses, respectively. H51Y did not change the susceptibility to dolutegravir, but G188R and H51Y+G118R conferred 7- and 28-fold resistance, respectively. This case illustrates how poorly-fit drug-resistant viruses wax and wane alongside erratic treatment adherence and are easily misdiagnosed by Sanger sequencing. We recommend next-generation sequencing to improve the clinical management of incomplete virological suppression with dolutegravir.


Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-centre observational study.
We analysed the characteristics of abnormal electroencephalogram (EEG) patterns before, during, and 48 h after cardiac surgery in patients with heterogeneous congenital heart disease to assess their relationship to demographic and perioperative variables and to early patient outcomes. In 437 patients enrolled in a single centre, EEG was evaluated for background (including sleep-wake cycle) and discharge (seizures, spikes/sharp waves, pathological delta brushes) abnormalities. Clinical data (arterial blood pressure, doses of inotropic drugs, and serum lactate concentrations) were recorded every 3 h. Postoperative brain MRI was performed before discharge. Preoperative, intraoperative, and postoperative EEG was monitored in 139, 215, and 437 patients, respectively. Patients with a degree of preoperative background abnormalities (n=40) had more severe intraoperative and postoperative EEG abnormalities (P<0.0001). Intraoperatively, 106/215 (49.3%) patients progressed into an isoelectric EEG. Longer durations of isoelectric EEG were associated with more severe postoperative EEG abnormalities and brain injury on MRI (Ps≤0.003). Postoperative background abnormalities occurred in 218/437 (49.9%) patients, and 119 (54.6%) of them had not recovered after surgery. Seizures occurred in 36/437 (8.2%) patients, spikes/sharp waves in 359/437 (82.2%), and pathological delta brushes in 9/437 (2.0%). Postoperative EEG abnormalities correlated with degree of brain injury on MRI (Ps≤0.02). Demographic and perioperative variables were significantly correlated with postoperative EEG abnormalities, which in turn correlated with adverse clinical outcomes. Perioperative EEG abnormalities occurred frequently and correlated with numerous demographic and perioperative variables and adversely correlated with postoperative EEG abnormalities and early outcomes. The relation of EEG background and discharge abnormalities with long-term neurodevelopmental outcomes remains to be explored.


Effect of lipids on insect cell growth and expression of recombinant proteins in serum-free medium.
The lipid emulsion components of a serum-free insect cell medium were varied and evaluated for effects on cell growth and recombinant protein expression. The growth of High-Five(TM) cells was significantly affected by polyol Pluronic F-68 and Tween-80, but not by lipids. Pluronic was essential for cell growth, while Tween-80 was required to achieve maximum cell densities. A dose response effect was observed for Tween-80 with optimal cell growth at a concentration of 25 mg/l. Cholesterol had a minor effect on cell growth, but was essential for the expression of recombinant proteins. The expression of β-galactosidase (β-gal) was directly affected by cholesterol with optimal expression at a concentration of 5.4 mg/l. Vitamin E, important as an antioxidant to stabilize lipids, did not directly affect recombinant protein expression. Although lipids were not required for cell growth, the presence of lipids were required during the cell growth phase in order to achieve efficient infection with baculovirus. These studies help to define the important components, and range of concentrations, for lipid emulsions which can effectively replace serum in insect cell culture.


The development and application of coupled HPLC-TLC for pharmaceutical analysis.
Successful coupling of high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) facilitates correlation of the retention factor (Rf) of a component in a TLC separation with a peak observed in HPLC, thus eliminating the need for isolation of the component. Experiments were designed to optimize flow and spotting rates for typical HPLC mobile phases, evaluating such parameters as band broadening and on-plate loading. Also investigated were the application of flow splitting and semi-microbore HPLC columns. The problems encountered with the development of TLC plates upon which the HPLC eluent has been applied as a linear streak were studied, as were detection methods for the resulting spots. This paper describes the successful development of the technique, using model compounds of pharmaceutical interest.


Detection of single-copy genes by nonisotopic in situ hybridization on human chromosomes.
A technique of in situ hybridization on metaphase chromosomes with biotinylated DNA probes is described. This technique was used to localize unique DNA sequences on chromosomes and allowed a localization of two probes 1.8 and 1.3 kb long. The hybridization signal appears like two, twin, spots on the two sister chromatids, allowing a clear distinction from the background. Moreover a chromosomal localization is possible by counting a relatively small number of mitoses compared with the technique using 3H-labeled DNA probes.


Retinal Pigment Epithelial Detachment in Age-Related Macular Degeneration.
Retinal pigment epithelial detachment is defined as a separation of the retinal pigment epithelium from the inner collagenous layer of Bruch's membrane. It is a common manifestation in both dry and wet types of age-related macular degeneration. This review aims to provide a comprehensive guide to the pathophysiology, clinical and imaging characteristics, natural course and treatment of the various types of pigment epithelial detachments in order to assist in diagnosis and management of this important feature of age-related macular degeneration.


Toll-like receptor 9 mediates oral bacteria-induced IL-8 expression in gingival epithelial cells.
Previously, we reported that various oral bacteria regulate interleukin (IL)-8 production differently in gingival epithelial cells. The aim of this study was to characterize the pattern recognition receptor(s) that mediate bacteria-induced IL-8 expression. Among ligands that mimic bacterial components, only a Toll-like receptor (TLR) 9 ligand enhanced IL-8 expression as determined by ELISA. Both normal and immortalized human gingival epithelial (HOK-16B) cells expressed TLR9 intracellularly and showed enhanced IL-8 expression in response to CpG-oligonucleotide. The ability of eight strains of four oral bacterial species to induce IL-8 expression in HOK-16B cells, and their invasion capacity were examined in the absence or presence of 2% human serum. The ability of purified bacterial DNA (bDNA) to induce IL-8 was also examined. Six out of eight strains increased IL-8 production in the absence of serum. Usage of an endosomal acidification blocker or a TLR9 antagonist inhibited the IL-8 induction by two potent strains. In the presence of serum, many strains lost the ability to induce IL-8 and presented substantially reduced invasion capacity. The IL-8-inducing ability of bacteria in the absence or presence of serum showed a strong positive correlation with their invasion index. The IL-8-inducing ability of bacteria in the absence of human serum was also correlated with the immunostimulatory activity of its bDNA. The observed immunostimulatory activity of the bDNA could not be linked to its CpG motif content. In conclusion, oral bacteria induce IL-8 in gingival epithelial cells through TLR9 and the IL-8-inducing ability depends on the invasive capacity and immunostimulating DNA.


[Blood coagulation and fibrinolysis in ischemic heart disease. The relationship to risk factors].
The data on blood coagulation and fibrinolysis in patients with coronary heart disease are reviewed. The relationship of the coagulating and fibrinolytic systems with cardiovascular risk factors is analysed.


Therapeutic bronchoscopy vs. standard of care in acute respiratory failure: a systematic review.
We aimed to assess patient-important benefits and harms of therapeutic bronchoscopy vs. standard of care (no bronchoscopy) in critically ill patients with acute respiratory failure (ARF). We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) according to the Cochrane Handbook and GRADE methodology, including a predefined protocol (PROSPERO no. CRD42016046235). We included randomized clinical trials (RCTs) comparing therapeutic bronchoscopy to standard of care in critically ill patients with ARF. Two reviewers independently assessed trials for inclusion, extracted data and assessed risk of bias. Risk ratios (RR) with 95% confidence intervals (CI) were estimated by conventional meta-analysis. The risk of random errors was assessed by TSA. Exclusively patient-important outcomes were evaluated. We included five trials (n = 212); all were judged as having high risk of bias. There was no difference in all-cause mortality between therapeutic bronchoscopy and standard of care (TSA adjusted RR 0.39; 95% CI 0.14 to 1.07; I2 0%), and only 3% of the required information size had been accrued. There was no difference in ICU length of stay. A shorter duration of mechanical ventilation was suggested by conventional meta-analysis, however TSA highlighted that only 42% of the required information size had been accrued, indicating high risk of random errors. No trials reported data on adverse events, hospital length of stay, quality of life or performance status. The quantity and quality of evidence supporting therapeutic bronchoscopy in critically ill patients with ARF is very low with no firm evidence for benefit or harm.


The role of alpha 2-adrenoceptors of the medullary lateral reticular nucleus in spinal antinociception in rats.
We attempted to find out the role of alpha 2-adrenoceptors of the medullary lateral reticular nucleus (LRN) in antinociception in rats. Spinal antinociception was evaluated using the tail-flick test, and supraspinal antinociception using the hotplate test. Antinociceptive effects were determined following local electric stimulation of the LRN, and following microinjections of medetomidine (an alpha 2-adrenoceptor agonist; 1-10 micrograms), atipamezole (an alpha 2-adrenoceptor antagonist; 20 micrograms) or lidocaine (4%) into the LRN. The experiments were performed using intact and spinalized Hannover-Wistar rats with a unilateral chronic guide cannula. Electric stimulation of the LRN as well as of the periaqueductal gray produced a significant spinal antinociceptive effect in intact rats. Medetomidine (1-10 micrograms), when microinjected into the LRN, produced no significant antinociceptive effect in the tail-flick test in intact rats. However, following spinalization, medetomidine in the LRN (10 micrograms) produced a significant atipamezole-reversible antinociceptive effect in the tail-flick test. In the hot-plate test, medetomidine (10 micrograms) in the LRN produced a significant atipamezole-reversible increase of the paw-lick latency in intact rats. Microinjection of atipamezole (20 micrograms) or lidocaine alone into the LRN produced no significant effects in the tail-flick test. The results are in line with the previous evidence indicating that the LRN and the adjacent ventrolateral medulla is involved in descending inhibition of spinal nocifensive responses. However, alpha 2-adrenoceptors in the LRN do not mediate spinal antinociception but, on the contrary, their activation counteracts antinociception at the spinal cord level.(ABSTRACT TRUNCATED AT 250 WORDS)


Capsulectomy vs capsulotomy in total hip arthroplasty. Clinical outcomes and proprioception evaluation: Study protocol for a randomized, controlled, double blinded trial.
Patients affected by coxarthrosis may be treated surgically with total hip arthroplasty (THA). During the surgical intervention, the hip joint capsule can be completely removed, performing a capsulectomy. Otherwise it's possible to perform a capsulotomy, which allows for capsular conservation. Since there is no scientific evidence demonstrating the superiority of one method over the other, the choice whether to remove or conserve the capsule is at the surgeon's discretion and both procedures are actually accepted.The purpose of our study is to evaluate the differences in functional activities and proprioception in patients who underwent THA and capsulotomy with capsular conservation versus patients who underwent THA with capsulectomy. In order to compare the two surgical techniques of capsulotomy with capsular conservation and capsulectomy, we created a randomized, controlled, double-blind, single-centre, non-pharmacological, interventional, superiority, parallel-group trial. The primary outcome of our study is evaluated using the HOOS scale (Hip disability and Osteoarthritis Outcome Score). Secondary outcomes are: the proprioceptive sensitivity, the postoperative bleeding, the surgical time, the active range of motion, and the ability to walk, sit and stand. The proprioception study is carried out through active and passive repositioning tests. THA is performed through the minimally invasive direct anterior approach. The evaluation tests are carried out in the 15 days preceding the intervention (T0), at 50-day post-operative (T1), and finally at three months after surgery (T2). Considering that the hip joint capsule is innervated by proprioceptive nerve endings, while the psuedocapsule that replaces the native capsule following a THA with capsulectomy doesn't have any active neurophysiological role, we hypothesize that capsulotomy with capsular conservation at the time of primary THA may lead to better proprioception and therefore better functional recovery. ClinicalTrials.gov identifier: NCT02749058. Date of registration: 04/21/2016.


Evidence for liver disease preceding amino acid abnormalities in hereditary tyrosinemia.
In hereditary tyrosinemia, an autosomal recessive disorder of infants, it has been postulated that hepatic toxicity arising from defective degradation of tyrosine accounts for the severe liver disease that is a feature of this condition. We measured the concentration of alpha-fetoprotein, a marker for liver disease, and of amino acid in cord blood from three infants with hereditary tyrosinemia and found that the concentration of alpha-fetoprotein was greatly increased at birth, whereas the level of tyrosine was normal or not specifically elevated, and that hypertyrosinemia developed only postnatally. These results indicate that liver disease is prenatal in hereditary tyrosinemia and that therapy aimed at reduction of the elevated tyrosine level is unlikely to be of fundamental value.


Incidence and survival variations of upper tract urothelial cancer in Taiwan (2001-2010).
To assess temporal patterns and regional differences in the incidence rate, and factors associated with survival of urinary tract urothelial carcinoma. The medical records of 8830 patients with new diagnoses of urinary tract urothelial carcinoma in the years 2001-2010 were retrieved from Taiwan National databases. Temporal trends, regional disparity and related survival factors were evaluated using the Cochran-Armitage trend test, local Moran's I statistic and log-rank test, respectively. The annual urinary tract urothelial carcinoma incidence rates (standardized by age) were steady at approximately 3.14-3.41 per 100 000 person-years. Notably, women had a significantly higher annual urinary tract urothelial carcinoma incidence than men in most of the years studied (range of female-to-male annual standardized rate ratio: 2.08-3.25), and diabetes prevalence in urinary tract urothelial carcinoma increased significantly from 12.3% to 23.4% per year over the 10 years. High urinary tract urothelial carcinoma incidence cluster areas other than the latest endemic area of "blackfoot disease" were newly identified by local Moran's I statistic (P < 0.05). Furthermore, older age, male sex, end-stage kidney disease and more advanced tumor grade were associated with lower 5-year overall survival probabilities in the 2001-2015 cohort. The incidence and survival of urinary tract urothelial carcinoma over the decade 2001-2010 were different according to population and regional features. Various urinary tract urothelial carcinoma screening, prevention, treatment and care plans should be developed depending on age, sex, comorbidity and area of residence.


Molecular mechanisms of water transport in the eye.
The four major sites for ocular water transport, the corneal epithelium and endothelium, the ciliary epithelium, and the retinal pigment epithelium, are reviewed. The cornea has an inherent tendency to swell, which is counteracted by its two surface cell layers, the corneal epithelium and endothelium. The bilayered ciliary epithelium secretes the aqueous humor into the posterior chamber, and the retinal pigment epithelium transports water from the retinal to the choroidal site. For each epithelium, ion transport mechanisms are associated with fluid transport, but the exact molecular coupling sites between ion and water transport remain undefined. In the retinal pigment epithelium, a H+-lactate cotransporter transports water. This protein could be the site of coupling between salt and water in this epithelium. The distribution of aquaporins does not suggest a role for these proteins in a general model for water transport in ocular epithelia. Some water-transporting membranes contain aquaporins, others do not. The ultrastructure is also variable among the cell layers and cannot be fitted into a general model. On the other hand, the direction of cotransport in symporters complies with the direction of fluid transport in both the corneal epi- and endothelium, as well as the ciliary epithelium and retinal pigment epithelium.


Erratum: uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements.
[This corrects the article DOI: 10.3389/fimmu.2021.627926.].


Catalytic oxidation and deionization of nitrite and nitrate ions using mesoporous carbon-supported nano-flaky cobalt and nickel oxyhydroxides.
The composite electrode of NiCo oxide supported by porous carbon was synthesized for nitrite oxidation and nitrate electro-sorption. The crystal structure and chemical state of the Co and Ni oxyhydroxides which were precipitated on loofah-derived activated carbon (AC) using hypochlorite were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and BET surface area. The voltammetry showed that the redox couple of Co(II)/Co(III) and Ni(II)/Ni(III) as the mediator catalytically transferred the electrons of NO2-/NO3-; the Ni site had a relatively high transfer coefficient and diffusive current, while the Co site was better in the capacitive removal of the nitrite and nitrate compounds. A batch electrolysis of nitrite ions was operated under constant anodic potential mode (0 to + 1.5 V vs. Ag/AgCl) to assess the performance of the composite electrodes. The adsorption capacity of NiCo/AC (Ni = 5% and Co = 5% on AC by weight) was 23.5 mg-N g-1, which was twice that of AC substrate (7.5 mg-N g-1), based on a multilayer adsorption model. The steady-state kinetics of the consecutive reaction were derived to determine the rate steps of the electrochemical oxidation of NO2- and adsorption of NO3-.


A mutant in a major heat shock protein of Escherichia coli continues to show inducible thermotolerance.
Escherichia coli cells carrying the dnaK756 mutation, were inactivated at 52 degrees C faster than control cells. This suggests that the intact dnaK gene product plays a role in protecting the cell from lethal damage at 52 degrees C. The effect of the dnaK mutation on induced thermotolerance was examined. Prior heat shock at 42 degrees C greatly lowered the subsequent inactivation rate in both mutant and control cells. This result suggests that, although produced in large amounts in response to thermal stress, mutation in the DnaK protein has little or no effect on induced thermotolerance.


Gastro-oesophageal reflux during day case gynaecological laparoscopy under positive pressure ventilation: laryngeal mask vs. tracheal intubation.
This study aimed to evaluate whether or not the use of intermittent positive pressure ventilation via the laryngeal mask airway is associated with a higher risk of gastro-oesophageal reflux when compared with intermittent positive pressure ventilation via a tracheal tube in patients undergoing day case gynaecological laparoscopy in the head down position. Sixty healthy women were randomly allocated to receive either the laryngeal mask or cuffed tracheal tube for intra-operative airway maintenance. Using continuous oesophageal pH monitoring, four patients in the tracheal tube group and none in the laryngeal mask group had evidence of gastro-oesophageal reflux (as indicated by a decrease in oesophageal pH to below 4). The difference in the incidence of reflux did not achieve statistical significance (p = 0.11). In conclusion, we found no evidence to suggest that the use of intermittent positive pressure ventilation via the laryngeal mask increases the risk of gastro-oesophageal reflux in patients undergoing elective day case gynaecological laparoscopy.


Inhibition of human UDP-glucose dehydrogenase expression using siRNA expression vector in breast cancer cells.
UDP-glucose dehydrogenase (UGDH) catalyzes two oxidations of UDP-glucose to yield UDP-glucuronic acid. Pathological over-production of extracellular matrix components may be linked to the availability of UDP-glucuronic acid, therefore UGDH is a potential therapeutic target. RNA interference (RNAi) has been adapted to knock down the expression of human UGDH. A UGDH siRNA plasmid was constructed using a pRNA-U6.1/Neo vector and transfected into breast cancer cells, ZR-75-1, with an efficiency of up to 50%. Western blot analysis showed that the UGDH expression was efficiently knocked down at protein levels by RNAi in ZR-75-1 cells.


Factors affecting adverse event reporting during mass ivermectin treatment for onchocerciasis.
This study examines the effect of age, sex, dosing round, time of day, and distance from the nurse monitor on adverse event reporting during mass ivermectin administration at Achi, south-east Nigeria. There was a significant increase in adverse event reporting with age but no significant difference between the sexes. Both compliance and the incidence of reported adverse events were less during the second dosing round than during the first. Only three (2%) out of 144 subjects interviewed gave adverse events as a reason for non-compliance. Significantly fewer adverse events were reported as starting at night (22:00-06:00 h) than by day. The effect of distance on adverse event reporting was not statistically significant for distances up to 1 km.


Blood pressure and autonomic responses following isolated and combined aerobic and resistance exercise in hypertensive older women.
This study aimed to compare blood pressure (BP) after isolated and combined sessions of aerobic and resistance exercises in hypertensive older women. Heart rate (HR) and heart rate variability (HRV) were included as additional variables. Twenty-one older women (63±1.9 years; 69.9±2.7 kg; 158.8±2.1 cm) with controlled hypertension (resting BP = 132.2 ± 3.1/74.1 ± 4.0 mmHg) performed four random sessions on different days: 1) aerobic exercise (AE: treadmill walking/running; 40 min; 50-60% HRreserve); 2) resistance exercise (RE: 8 exercises; 3 sets; 15 reps; 40% 1RM)); 3) aerobic exercise followed by resistance exercise (A+R); 4); control (CON). BP, HR and HRV were measured at rest and during 180 min after the sessions. The AE and A+R sessions demonstrated significant decreases in SBP and DBP (30, 60, 120, and 180 min; P < 0.05) and increases in HR (30 and 60 min; P < 0.05) compared to the CON. The RE session demonstrated significant reductions compared to the CON only for DBP (120 and 180 min; P < 0.05). No significant differences were observed in HRV between resting and all sessions. All sessions that involved aerobic exercise (AE and A+R) caused postexercise hypotension in comparison to the CON, with no differences in HRV.


Implicit Racial Bias, Health Care Provider Attitudes, and Perceptions of Health Care Quality Among African American College Students in Georgia, USA.
Due to racism, over 20% of African Americans, including college students in Georgia, receive poor quality health care. Consequently, most students are reluctant to utilize health care services in the state. This study examined biased racial attitudes of health care providers in Georgia, and African American Georgia State University (GSU) School of Public Health (SPH) students' perceptions of the quality of health care they receive from providers, the effects of such care, and student recommendations for the way forward. A mixed-methods cross-sectional design was used to collect data from 63 students across six domains using Qualtrics. Provider brushes off patient concerns when providing medical care (29.9%), stereotyping (26.9%), and the lack of communication during medical care (25.4%) were the three main implicit racial attitudes identified by GSU SPH students. Owing to the poor quality of care they receive from their health care providers, some students (28.4%) are reluctant to utilize health care services, distrust doctors that are not from their race (34.3%), do not adhere to treatment (19.4%), and prefer to use home remedies (28.4%) when ill. Students recommended cultural competency training, holding health care providers accountable for their actions, and increasing African American health care providers in Georgia as ways to address health care provider attitudes and quality of care. Negative provider attitudes impact the health and health-seeking behavior of African American college students in Georgia. These attitudes must be eliminated so barriers to clinical participation are removed, and student health outcomes optimized.


Mitigating membrane fouling by coupling coagulation and the electrokinetic effect in a novel electrocoagulation membrane cathode reactor.
Membrane reactors with efficient antifouling and low maintenance are desirable for distributed membrane water treatment. In this study, a novel membrane separation reactor with an Al anode and a conductive membrane as the cathode was built to develop a chemical-free method for mitigating membrane fouling via electrocoagulation coupled with the electrokinetic effect. The electrostatic repulsion between humic acid (HA) and the membrane cathode reduced the adhesion of HA foulants on the membrane, thereby contributing to antifouling in the initial stage. Electrocoagulation and polarization induced by the electric field enlarged the HA-Al flocs, which prevented membrane pore blocking and facilitated the formation of a porous cake layer, thereby leading to a high water flux of the electrocoagulation membrane cathode reactor (ECMCR) in the stable stage. The bubbles from hydrogen evolution on the membrane cathode scoured the HA foulants and washed out the dense cake layer, thereby playing an important role in membrane fouling mitigation. Compared with membrane filtration, the membrane cathode reactor, membrane anode reactor, and HA removal of the ECMCR increased by 9.6, 8.3, and 2.8 times, respectively, whereas the transmembrane pressure decreased by 84.6%, 21.5%, and 63.0%, respectively. The synergy of electrocoagulation and the electrokinetic effect provides the ECMCR with a feasible method of antifouling and improved effluent quality with low maintenance.


Medical students' knowledge, perceptions, and behavioral intentions towards the H1N1 influenza, swine flu, in Pakistan: a brief report.
This study was conducted to assess the knowledge of H1N1 among medical students, their perceptions, and behavioral intentions in the wake of the H1N1 pandemic influenza. There were significant gaps in important self-isolation protocols and preventive measures. Increased contact with both patients and colleagues can lead to unintentional transmission and contraction of influenza. Universities should introduce and encourage infection control guidelines into routine curriculum.


Multiple and spectrally robust photonic magic angles in reconfigurable α-MoO3 trilayers.
The emergence of a topological transition of the polaritonic dispersion in twisted bilayers of anisotropic van der Waals materials at a given twist angle-the photonic magic angle-results in the diffractionless propagation of polaritons with deep-subwavelength resolution. This type of propagation, generally referred to as canalization, holds promise for the control of light at the nanoscale. However, the existence of a single photonic magic angle hinders such control since the canalization direction in twisted bilayers is unique and fixed for each incident frequency. Here we overcome this limitation by demonstrating multiple spectrally robust photonic magic angles in reconfigurable twisted α-phase molybdenum trioxide (α-MoO3) trilayers. We show that canalization of polaritons can be programmed at will along any desired in-plane direction in a single device with broad spectral ranges. These findings open the door for nanophotonics applications where on-demand control is crucial, such as thermal management, nanoimaging or entanglement of quantum emitters.


A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.
Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.


Infective endocarditis in elderly patients.
Infective endocarditis (IE) in elderly patients presents a unique diagnostic and therapeutic challenge. Atypical presentations frequently lead to delayed diagnosis and poor outcome. IE in elderly persons is somewhat more common among men. Underlying degenerative valvular disease, mitral valve prolapse, and the presence of a prosthetic valve are important risk factors predisposing elderly persons to IE. Streptococci and staphylococci are the predominant organisms, which are recovered from approximately 80% of elderly patients with IE. In older patients, IE occurs somewhat more frequently on the mitral valve than it does on the aortic valve. The presence of calcific valvular lesions and the prosthetic valves often confound the echocardiographic findings in elderly patients. A high index of suspicion and an aggressive diagnostic approach are required to ensure timely diagnosis and appropriate therapy.


ATP-induced activation of purified rat hepatic glucocorticoid receptors.
We have utilized unactivated rat hepatic glucocorticoid receptor complexes purified to near homogeneity by a three-step scheme which includes affinity chromatography, gel filtration and anion exchange chromatography, to demonstrate for the first time that ATP can interact directly with the receptor protein in stimulating activation. This stimulation is reflected by an increase in DNA-cellulose binding as well as by a shift in the elution profile of the purified receptor complexes from DEAE-cellulose. A concentration of 10 mM Na2MoO4 is able to block both of these effects. ATP stimulates activation in a dose-dependent manner (maximally at 10 mM), and elicits maximal activation within 30 min at 15 degrees C. There appears to be no nucleotide specificity since GTP, CTP and UTP, as well as ADP and GDP also stimulate activation. All of these observations closely parallel data obtained from similar activation experiments performed with crude rat hepatic receptors. ATP does not appear to stimulate activation of receptors (crude or purified) by initiating a phosphorylation reaction since hydrolysis-resistant analogues of ATP are also effective. Pyrophosphate (PPi) is as effective as ATP in promoting receptor activation, since it elicits similar increases in DNA-cellulose binding, shifts in elution patterns from DEAE-cellulose, and dose-response relationships. None of the compounds tested stimulate activation indirectly by pH or ionic strength effects. Despite the fact that high ATP concentrations (3-4-fold higher than those present in vivo) are necessary to stimulate maximal activation, a physiological role of ATP in directly regulating in vivo activation of glucocorticoid receptors cannot be ruled out.


Effect doses for protection of human health predicted from physicochemical properties of metals/metalloids.
Effect doses (EDs) of metals/metalloids, usually obtained from toxicological experiments are required for developing environmental quality criteria/standards for use in assessment of hazard or risks. However, because in vivo tests are time-consuming, costly and sometimes impossible to conduct, among more than 60 metals/metalloids, there are sufficient data for development of EDs for only approximately 25 metals/metalloids. Hence, it was deemed a challenge to derive EDs for additional metals by use of alternative methods. This study found significant relationships between EDs and physicochemical parameters for twenty-five metals/metalloids. Elements were divided into three classes and then three individual empirical models were developed based on the most relevant parameters for each class. These parameters included log-βn, ΔE0 and Xm2r, respectively (R2 = 0.988, 0.839, 0.871, P < 0.01). Those models can satisfactorily predict EDs for another 25 metals/metalloids. Here, these alternative models for deriving thresholds of toxicity that could be used to perform preliminarily, screen-level health assessments for metals are presented.


In vitro inhibition of goat brain acetylcholinesterase by pure and commercial anticholinesterase pesticides.
In vitro inhibition of goat cerebellar acetylcholinesterase by pure and commercial anticholinesterase pesticides clearly indicates a remarkably high inhibitory effect of commercial carbamate and organophosphate pesticides containing a lower percentage of the respective active ingredients comparable to that of the known anticholinesterase agents such as DFP and physostigmine. It may be presumed that injudicious use of commercial formulations conduce severe toxicity in the nontarget mammalian species, namely, goat, and this response of the brain acetylcholinesterase may be utilized as a reliable bioindicator of pesticidal contamination of the terrestrial environment.


Correction to: Why Do Reoperation Rates Vary So Much After Lumpectomy for Breast Cancer? Examining the Reoperation Puzzle.
In the original article the correct citation for where Massachusetts General Hospital (MGH) is mentioned throughout the text.


Clinical features as predictors of histologically confirmed inflammation in patients with lumbar disc herniation with associated radiculopathy.
An understanding of the clinical features of inflammation in low back pain with or without leg symptoms may allow targeted evaluations of anti-inflammatory treatment in randomised-controlled-trials and clinical practice. This study evaluated the diagnostic accuracy of clinical features to predict the presence/absence of histologically confirmed inflammation in herniated disc specimens removed at surgery in patients with lumbar disc herniation and associated radiculopathy (DHR). Cohort Study. Disc material from patients with DHR undergoing lumbar discectomy was sampled and underwent histological/immunohistochemistry analyses. Control discs were sampled from patients undergoing surgical correction for scoliosis. Baseline assessment comprising sociodemographic factors, subjective examination, physical examination and psychosocial screening was conducted and a range of potential clinical predictors of inflammation developed based on the existing literature. Multi-variate analysis was undertaken to determine diagnostic accuracy. Forty patients with DHR and three control patients were recruited. None of the control discs had evidence of inflammation compared to 28% of patients with DHR. Predictors of the presence of histologically confirmed inflammation included back pain < 5/10, symptoms worse the next day after injury, lumbar flexion range between 0 and 30° and a positive clinical inflammation score (at least 3 of: constant symptoms, morning pain/stiffness greater than 60-min, short walking not easing symptoms and significant night symptoms). The model achieved a sensitivity of 90.9%, a specificity of 92.9%, and a predictive accuracy of 92.3%. In a sample of patients with lumbar DHR a combination of clinical features predicted the presence or absence of histologically confirmed inflammation. These clinical features may enable targeted anti-inflammatory treatment in future RCTs and in clinical practice.


Delayed formation of the floor plate after ablation of the avian notochord.
We have examined the long-term effects of notochord ablation at chick stages 9-10 on formation of the floor plate and motor neurons. Although missing or reduced 2 days postablation, the floor plate and motor neurons were morphologically normal by 4 postoperative days. When isolated whole or ventral, but not lateral, neural plate fragments from stage 9 embryos were cultured for 4 days in collagen gels, floor plate and neural markers were observed. Our results suggest that floor plate and motor neurons can form in a delayed fashion in vivo after notochord ablation and in vitro from isolated neural plates. This suggests that either there is an early induction of floor plate by the chordamesoderm of Hensen's node, or only limited interactions between the neural plate and notochord immediately after neurulation are required for floor plate determination.


Global assessment of cadmium concentrations in the skin of free-ranging sperm whales (Physeter macrocephalus).
Cadmium is a non-essential, toxic metal found accumulated in the organs of stranded cetaceans. Currently, there is no baseline cadmium concentration reported in a free-ranging, pelagic cetacean. The aim was to determine cadmium concentrations in the skin of free-ranging sperm whales (n=340) collected from 16 regions around the world during the voyage of the Odyssey (2000-2005) considering region, gender, and age in males. Cadmium was detected in 81% of skin biopsies with a mean of 0.3±0.04μg/g ww (0.02 to 12.4μg/g ww). These concentrations were higher than reported in literature in toothed whale skin (0.002-0.1μg/g ww). Concentrations by region were significantly different (p<0.0001) with the highest mean in Maldives and the Sea of Cortez (0.8 and 0.6μg/g ww, respectively). There was no significant difference in cadmium concentration by gender (p=0.42). Cadmium is known to have a long biological half-life, and cadmium concentrations in males were significantly higher in adults with a mean of 0.3μg/g ww compared to subadults with 0.2μg/g ww (p=0.03). Selenium, an element that binds to cadmium inhibiting its toxicity, had a moderately positive correlation with cadmium (r=0.41). Mercury, a toxic metal that positively correlates with cadmium in cetacean tissue, had a weakly positive relationship (r=0.20). The regional baselines reported in this study may be used to develop residue criteria for prediction of toxicological risk in sperm whale skin. Additionally, this study shows the extent of cadmium exposure in a pelagic cetacean that has global distribution.


Geographic variation in amputation rates among patients with diabetes and/or peripheral arterial disease in the rural state of West Virginia identifies areas for improved care.
Amputation is a devastating but preventable complication of diabetes and peripheral arterial disease (PAD). Multiple studies have focused on disparities in amputation rates based on race and socioeconomic status, but few focus on amputation trends in rural populations. The objective of this study was to identify the prevalence of major and minor amputation among patients admitted with diabetes and/or PAD in a rural, Appalachian state, and to identify geographic areas with higher than expected major and minor amputations using advanced spatial analysis while controlling for comorbidities and rurality. Patient hospital admissions of West Virginia residents with diagnoses of diabetes and/or PAD and with or without an amputation procedure were identified from the West Virginia Health Care Authority State Inpatient Database from 2011 to 2016 using relevant International Classification of Diseases, 9th edition and 10the edition codes. Bayesian spatial hierarchical modeling was conducted to identify areas of high risk, while controlling for important confounders for amputation. Overall, there were 5557 amputations among 459,452 hospital admissions with diabetes and/or PAD from 2011 to 2016. The majority of the amputations were minor (61.7%; n = 3430), with a prevalence of 7.5 per 1000 and 40.4% (n = 2248) were major, with a prevalence of 4.9 per 1000. Geographic analysis found significant variation in risk for both major and minor amputation across the state, even after adjusting for the prevalence of risk factors. Analyses indicated an increased risk of amputation in the central and northeastern regions of West Virginia at the county level, although zip code-level patterns of amputation varied, with high-risk areas identified primarily in the northeastern and south central regions of the state. There is significant geographic variation in risk of amputation across West Virginia, even after adjusting for disease-related risk factors, suggesting priority areas for further investigation. The level of granularity obtained using advanced spatial analyses rather than traditional methods demonstrate the value of this approach, particularly when risk estimates are used to inform policy or public health intervention.


Mapping the promoter for subgenomic RNA synthesis on beet necrotic yellow vein virus RNA 3.
During infection of Tetragonia expansa leaves, RNA 3 of the quadripartite genome of beet necrotic yellow vein virus directs synthesis of a subgenomic RNA (RNA 3sub) which corresponds to the 3'-terminal 600 residues of the RNA 3 molecule. Biologically active run-off transcripts have been prepared from full-length cDNA of RNA 3 cloned behind a bacteriophage T7-RNA polymerase promoter. RNA 3 transcripts carrying deletions in the vicinity of the RNA 3sub initiation site were produced by site-directed mutagenesis at the cDNA level and then tested for their capacity to direct RNA 3sub synthesis in infected leaves. The cis-acting domain essential for normal levels of RNA 3sub production in planta (the 'core' promoter) did not extend in the 5'-direction beyond position -16 relative to the RNA 3sub transcription initiation site. The 3'-boundary of the core promoter domain was located somewhere between positions +100 and +208. Displacement of the promoter domain to an upstream site in RNA 3 produced a new subgenomic RNA starting at or near the predicted upstream site.


Anterior lamellar repositioning with complete lid split: a modified method for treating upper eyelids trichiasis in Asian patients.
Anatomically, the upper eyelids of an Asian are considerably unique, and nearly half of the East Asians have single eyelids. This study presents a new, modified, Asian-specialised procedure to simultaneously treat trichiasis and dermatochalasis. It combines anterior lamellar repositioning with lid split surgery and blepharoplasty, and creates a completely penetrating anterior lamellar flap so as to fully shift the anterior lid margin upwards. Between May 2004 and May 2006, 114 cases (144 eyelids) were operated and followed-up for at least 12 months. Lid margin and eyelash position, improvement of symptoms, recurrence rate, overcorrection and aesthetic appearance were assessed at each visit. Of the 144 eyelids operated, the recurrence rate was 0% at 3 months, 2.8% at 6 months and 5.6% at 12 months. There was no case of secondary lid ectropion or retraction, and the aesthetic alterations were accepted by all the patients. In conclusion, the modified operation - anterior lamellar repositioning with complete lid split - is an effective, personalized method for the treatment of upper eyelids trichiasis in Asian patients.


OsWRKY IIa Transcription Factors Modulate Rice Innate Immunity.
WRKY transcription factors regulate diverse plant processes including responses to biotic stresses. Our previous studies indicate that OsWRKY62, an OsWRKY IIa subfamily member, functions as a negative regulator of the rice defense against Xanthomonas oryzae pv. oryzae. Here, we report that a large inverted repeat construct designed to knock down the expression of the four OsWRKY IIa subfamily members (OsWRKY62, OsWRKY28, OsWRKY71, and OsWRKY76) leads to overexpression of all four genes and disease resistance in some transgenic plants. These phenotypes are stably inherited as reflected by progeny analysis. A pathogenesis-related gene, PR10, is up-regulated in plants overexpressing the OsWRKY IIa genes. These results suggest that OsWRKY IIa proteins interact functionally to modulate plant innate immunity.


Numerical simulation of roof cavings in several Kuzbass mines using finite-difference continuum damage mechanics approach.
An essential stage of mine design is an estimation of the steps of the first and periodic roof caving in longwall mines. Generally, this is carried out using the field experience and can be much enhanced by numerical simulation. In this work, the finite-difference method was applied coupled with the continuum damage mechanics (CDM) approach to simulate the stress-strain evolution of the rock mass with the underground opening during coal extraction. The steps and stages of roof caving were estimated relying on the numerical simulation data, and they were compared with the field data from several operating mines in the south of the Kuznetsk Basin, Russia. The dependence of the first roof caving step in simulation linearly correlates with field data. The results correspond to the actual roofs of longwall panels of the flat-dipping coal seams and the average rate of face advancement is approximately 5 m/day.


Optimization of chitosan/tannic acid@ ZnFe layered double hydroxide bionanocomposite film for removal of reactive blue 4 using a response surface methodology.
Layered double hydroxides (LDH) are great adsorbents for anionic pollutants, but are in a powder form that leads to challenges in solid-liquid separation, low hydraulic conductivity, and handling. Herein, novel bionanocomposite films containing chitosan (Cs), tannic acid (TA), and LDH were fabricated and applied for the removal of reactive blue 4 (RB4). A response surface methodology with Box-Behnken design was applied to study the effect of operating parameters (TA%: 0-20, LDH%: 0-20, pH: 5-9, adsorbent dosage: 0.5-1.5 g L-1, time: 30-90 min) on RB4 dye removal (DR%). A quadratic regression equation was successfully developed to predict the response (R2: 0.95). The obtained optimized condition was TA%: 10, LDH%: 20, pH: 5, adsorbent dosage: 1.5 g L-1, and time: 71 min that resulted in DR%: 98.2. The best-fitted adsorption isotherm and kinetic models were linear Langmuir and nonlinear pseudo-second-order models, respectively. The maximum capacity of adsorption for the optimized film was 406 mg g-1. The obtained thermodynamic parameters implied that the process of adsorption was exothermic and spontaneous. The reusability studies showed that the DR% was decreased from 93% for the first cycle to 69%, 57%, and 56% for the second, third and fourth cycle, respectively.


Nurses' roles in discharge decision making in an adult high dependency unit.
An ethnographic approach was used to investigate the roles which nurses take in the discharge decision making process in an adult High Dependency Unit (HDU). Participant observation and unstructured interviews were the data collection methods used. Four themes were identified. The first theme encompassed the relationship of nurses with medical staff. Tension was felt between nursing and medical staff, although this was not demonstrated in direct communication between the two professions. Nurses took a submissive role in order to avoid conflict, but this also enabled them to manipulate doctors. Another theme was the unique value of the nurse which was defined as the 'holistic' view which nurses took towards patients which was different to that taken by other health care professionals. Nurses undertook an important administrative role. They had substantial responsibility for bed management and became more proactive in decision-making when there was pressure on HDU beds. Issues associated with decision making were highlighted, as although nurses wanted to contribute to discharge decision making, they were often uncomfortable with this role. There is scope for further investigation into the working relationship of nurses and medical staff, how administrative roles of nurses influence their ability to provide patient care and whether the opinions expressed with regard to decision making are widespread within the nursing community.


Neural cell adhesion molecule distribution in soft tissue tumors.
The distribution of the neural cell adhesion molecule (N-CAM; CD56) was studied immunohistochemically in acetone-fixed frozen sections of 83 soft tissue tumors and selected normal mesenchymal tissue using Leu-19 monoclonal antibody and avidin-biotin peroxidase immunostaining. Positive N-CAM immunostaining was found in gastrointestinal and uterine cells but not in vascular smooth muscle cells. Normal skeletal muscle was negative, but atrophic muscle fibers within tumors were positive. Strong and consistent immunoreactivity was seen in nerves, pheochromocytoma, malignant schwannoma, and spindle cells, but not in epithelial-like cells of synovial sarcoma, hemangiopericytoma, benign leiomyoma, and rhabdomyosarcoma. Variable staining was seen in benign schwannoma and malignant fibrous histiocytoma. Limited, usually focal N-CAM immunoreactivity was seen in desmoid tumor, dermatofibrosarcoma, and leiomyosarcoma. Although the N-CAM is consistently seen in neural tumors, it is not cell lineage specific. Changes on malignant transformation (comparing corresponding benign and malignant lesions) do not show any consistent pattern. Rather, there is neoexpression of the N-CAM in rhabdomyosarcoma, whereas there is loss of the N-CAM in leiomyosarcoma. Immunohistochemistry of the N-CAM can be a useful adjunct for characterization of soft tissue tumors, and its possible correlation with tumor behavior has to be examined in further studies.


Perfectionism, narcissism, and depression in suicidal and nonsuicidal adolescent inpatients.
The aim of this study was to investigate the relationship between 2 psychological profiles: (a) the intrapersonal profile, involving self-critical depression, self-oriented perfectionism, and narcissism, and (b) the interpersonal profile, involving dependent depression and socially prescribed perfectionism, and the association of these 2 profiles with suicidal behavior among adolescent inpatients. One hundred adolescents, admitted to a university-affiliated psychiatric adolescent inpatient unit in Israel, completed the Depressive Experience Questionnaire for Adolescents, the Child and Adolescent Perfectionism Scale, and the Narcissistic Personality Inventory. The Suicidal Potential Interview was used to evaluate suicidal behavior and separate them into low-risk and high-risk groups. Dependent depression correlated positively and significantly with severity of suicidal behavior. Adolescent inpatients with high levels of suicidal behavior (n = 54) were more dependent in terms of depression and were more inclined to socially prescribed perfectionism compared with adolescent inpatients with low levels of suicidal behavior (n = 45). The components of the intrapersonal profile did not correlate with severity of suicidal behavior; however, low narcissism scores characterized the psychological function that strongly predicted severe suicidal behavior. The findings indicated that the conceptualization of 2 broad intrapersonal and interpersonal profiles in adolescent inpatients may have some validity in terms of the interpersonal dimension. The components of the interpersonal profile related to severe suicidal behavior and may be important in planning treatment strategy.


Improvement of visual scanning after DC brain polarization of parietal cortex in stroke patients with spatial neglect.
Previous studies have demonstrated that transcranial direct current (DC) brain polarization can modulate cortical excitability in the human brain. We investigated the effect of anodal DC brain polarization of right parietal cortex on visuospatial scanning in subacute stroke patients with spatial neglect. The patients underwent two neglect tests - figure cancellation and line bisection - before and immediately after anodal DC or sham in a double-blind protocol. Anodal DC was applied to the scalp over the right posterior parietal cortex (PPC) with an intensity of 2.0 mA for 20 min. Anodal DC brain polarization, but not sham, led to significant improvement in the both neglect tests. These results document a beneficial effect of DC brain polarization on neglect.


Lead failure in transvenous implantable cardioverter defibrillator: a new opportunity for an effective management.
In case of transvenous defibrillator lead failure, a subcutaneous defibrillator may be implanted and the lead may be abandoned in order to avoid particular risk situations. For patients who require pacing and with an operational atrial lead, the transvenous ICD may be also maintained to ensure antibradycardia support.


Screening and identification of the metabolites in rat urine and feces after oral administration of Lycopus lucidus Turcz extract by UHPLC-Q-TOF-MS mass spectrometry.
Lycopus lucidus Turcz has been used as a kind of edible and medicinal material in eastern Asian countries. It has various bioactivities, including treatment of menstrual disorder, amenorrhea, menstrual cramps, inflammation, and cardiovascular diseases. However, the in vivo metabolism of L. lucidus Turcz extract is still not well described. In this study, L. lucidus Turcz extracts were administered to rats. Urine and fecal samples were collected at the difference periods (0-12h, 12-24h, and 24-36h). Ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was developed to characterize and identify the metabolites. A total of 17 metabolites in feces and 19 metabolites in urine were tentatively identified by means of accurate mass and characteristic fragment ions. The results show that glucuronidation and sulfation are the major metabolic reactions. This study is the first reported analysis and characterization of the metabolites and the proposed metabolic pathways of bioactive components might provide further understanding of the metabolic fate of the chemical constituents after oral administration of L. lucidus Turcz extract in rats.


Omic-profiling in breast cancer metastasis to bone: implications for mechanisms, biomarkers and treatment.
Despite well-recognised advances in breast cancer treatment, there remain substantial numbers of patients who develop metastatic disease, of which up to 70% involves spread to bone, resulting in skeletal complications which have a major negative impact on mortality and quality of life. Bisphosphonates and newer bone-targeted agents have reduced the prevalence of skeletal complications, yet there remains significant unmet clinical need, particularly for the development of more specific therapies for the prevention and treatment of metastatic bone disease, for the prediction of risk of its development in individual patients and for the prediction of response to treatments. Modern 'omic' strategies can potentially make a major contribution to meeting this need. Technological advances in the field of nucleic acid sequencing, mass spectrometry and metabolic profiling have driven progress in genomics, transcriptomics (functional genomics), proteomics and metabolomics. This review appraises the recent application of these approaches to studies of breast cancer metastasis (particularly to bone), with a focus on understanding how omic approaches may lead to new therapeutic options and to novel biomarker molecules or molecular signatures with potential value in clinical practise. The increasingly recognised need for rigorous sample quality control and both pre-clinical and clinical validation to meet the ultimate goals of clinical utility and patient benefit is discussed. Future directions of omic driven research in breast cancer metastasis are considered, in particular micro-RNAs and their role in the post-transcriptional regulation of gene function and the possible role of cancer-stem cells and epigenetic modifications in the development of distant metastases.


The prognostic relevance of FOXA1 and Nestin expression in breast cancer metastases: a retrospective study of 164 cases during a 10-year period (2004-2014).
Current prognostic markers cannot adequately predict the clinical outcome of breast cancer patients. Therefore, additional biomarkers need to be included in routine immune panels. FOXA1 was a significant predictor of favorable outcome in primary breast cancer, while Nestin expression is preferentially found in triple-negative tumors with increased rate of nodal metastases, and reduced survival. No studies have investigated the prognostic value of FOXA1 and Nestin expression in breast cancer metastases. Breast cancer metastases (n = 164) from various anatomical sites were retrospectively analyzed by immunohistochemistry for FOXA1, Nestin and GATA3 expression. Cox regression analysis assessed the prognostic value of FOXA1 and Nestin expression. In breast cancer metastases, FOXA1 expression was associated with Nestin-negativity, GATA3-positivity, ER-positivity, HER2-positivity and non-triple-negative status (P < 0.05). In contrast, Nestin expression was associated with FOXA1-negative, GATA3-negative, ER-negative, and triple-negative metastases (P < 0.05). Univariate Cox regression analysis showed FOXA1 expression was predictive of overall survival (OS, P = 0.00048) and metastasis-free survival (DMFS, P = 0.0011), as well as, distant metastasis-free survival in ER-positive patients (P = 0.036) and overall survival in ER-negative patients (P = 0.024). Multivariate analysis confirmed the significance of FOXA1 for both survival endpoints in metastatic breast cancer patients (OS, P = 0.0033; DMFS, P = 0.015). In our study, FOXA1 was expressed mostly in ER-positive breast cancer metastases. Expression of Nestin was related to triple-negative metastases, where brain was the most frequent metastatic site. These findings highlight the clinical utility of FOXA1 and Nestin expression and warrant their inclusion in routine immunohistochemical panels for breast carcinoma.


Validity of a clinical scale in predicting the failure of non-invasive ventilation in hypoxemic patients.
The HACOR scale is a clinical score that can predict early failure of NIV in hypoxemic acute respiratory failure (ARF) The aim of this study is to analyze the validity of the HACOR scale. A retrospective study of a cohort of over 2749 episodes on 2711 consecutive patients requiring NIV for hypoxemic ARF in a polyvalent intensive care unit. The scale was measured before starting NIV and at 1, 6, 12, 24 and 48 h after the initiation of NIV. NIV failure occurred in 963 patients (35%). The value of the HACOR scale before NIV did not differ between success and failure. However, at 1, 6, 12, 24 and 48 h of NIV, the scale values clearly differed between the two groups. The HACOR scale at NIV initiation accurately predicts NIV failure in the first hour, with an optimal cut-off value of 8 points. The AUC for predicting NIV failure with HACOR at 1 h is greater than 0.9 in patients with pneumonia and adult respiratory distress syndrome (ARDS). The HACOR scale measured at 1 h after NIV initiation accurately predicts NIV failure, especially in pneumonia and ARDS.


[Complete Rupture of the Extensor Hallucis Longus Tendon with Accessory Slip Mimicking a Partial Rupture: A Case Report].
The accessory tendon of the extensor hallucis longus is a common type of extensor hallucis longus variation. This is a case of a 38-year-old female patient who initially considered conservative treatment for a suspected partial rupture, but finally underwent surgery after being diagnosed with a complete rupture of the main tendon and accessory tendon medial to the main tendon on MRI scan.


Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.
To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.


Speech recognition in individuals with sensorineural hearing loss.
Hearing loss can negatively influence the communication performance of individuals, who should be evaluated with suitable material and in situations of listening close to those found in everyday life. To analyze and compare the performance of patients with mild-to-moderate sensorineural hearing loss in speech recognition tests carried out in silence and with noise, according to the variables ear (right and left) and type of stimulus presentation. The study included 19 right-handed individuals with mild-to-moderate symmetrical bilateral sensorineural hearing loss, submitted to the speech recognition test with words in different modalities and speech test with white noise and pictures. There was no significant difference between right and left ears in any of the tests. The mean number of correct responses in the speech recognition test with pictures, live voice, and recorded monosyllables was 97.1%, 85.9%, and 76.1%, respectively, whereas after the introduction of noise, the performance decreased to 72.6% accuracy. The best performances in the Speech Recognition Percentage Index were obtained using monosyllabic stimuli, represented by pictures presented in silence, with no significant differences between the right and left ears. After the introduction of competitive noise, there was a decrease in individuals' performance.


Long-term persistence of piscine orthoreovirus-1 (PRV-1) infection during the pre-smolt stages of Atlantic salmon in freshwater.
Piscine orthoreovirus (PRV) causes heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon. During salmon production cycles, HSMI has predominantly been observed after seawater transfer. More recently, better surveillance and longitudinal studies have detected occurrences of PRV-1 in freshwater broodstock farms and hatcheries. However, very little is known about the viral kinetics of PRV-1 or disease development of HSMI during these pre-smolt stages. In this study, we conducted a long-term PRV-1 challenge experiment to examine the profile of viral load, infectiousness and/or clearance in Atlantic salmon during their development from fry to parr stage. Atlantic salmon fry (mean weight: 1.1 ± 0.19 g) were infected with PRV-1 (high virulent variant) via intraperitoneal (IP) injection. The viral load reached a peak at 2-4 weeks post-challenge (wpc) in heart and muscle tissues. The virus was detected at relatively high levels in whole blood, spleen, and head kidney tissues until 65 wpc. Heart and muscle lesions typical of HSMI were clearly observed at 6 and 8 wpc but then subsided afterwards resolving inflammation. Innate and adaptive immune responses were elicited during the early/acute phase but returned to basal levels during the persistent phase of infection. Despite achieving high viremia, PRV-1 infection failed to cause any mortality during the 65-week virus challenge period. Cohabitation of PRV-1 infected fish (10 and 31 wpc) with naïve Atlantic salmon fry resulted in very low or no infection. Moreover, repeated chasing stress exposures did not affect the viral load or shedding of PRV-1 at 26 and 44 wpc. The present findings provide knowledge about PRV-1 infection in juvenile salmon and highlight the importance of continued monitoring and management to prevent and mitigate the PRV-1 infection in freshwater facilities.


In vitro antiplasmodial activity of extract and constituents from Esenbeckia febrifuga, a plant traditionally used to treat malaria in the Brazilian Amazon.
Esenbeckia febrifuga (Rutaceae) is a plant traditionally used to treat malaria in the Brazilian Amazon region. Ethanol extract of stems displayed a good antiplasmodial activity against Plasmodium falciparum strains W-2 (IC(50) 15.5+/-0.71 microg/ml) and 3 D7 (IC(50) 21.0+/-1.4 microg/ml). Two coumarins (bergaptene 1 and isopimpinellin 2), five alkaloids (flindersiamine 3, kokusaginine 4, skimmiamine 5, gamma-fagarine 6 and 1-hydroxy-3-methoxy-N-methylacridone, 7), besides a limonoid (rutaevine 8), have been isolated for the first time from this species. Antiplasmodial activity of compounds 3, 5-8 has been evaluated in vitro against P. falciparum strains (W-2 and 3D7) and the furoquinolines 5 and 6 were the most potent displaying IC(50) values <50 microg/ml; flindersiamine (3) showed a weak activity while alkaloid 7 and rutaevine (8) were inactive (IC(50)>100 microg/ml).


Oxygen uptake kinetics and chronotropic responses to exercise are impaired in survivors of severe COVID-19.
The post-acute phase of coronavirus disease 2019 (COVID-19) is often marked by several persistent symptoms and exertional intolerance, which compromise survivors' exercise capacity. This was a cross-sectional study aiming to investigate the impact of COVID-19 on oxygen uptake (V̇o2) kinetics and cardiopulmonary function in survivors of severe COVID-19 about 3-6 mo after intensive care unit (ICU) hospitalization. Thirty-five COVID-19 survivors previously admitted to ICU (5 ± 1 mo after hospital discharge) and 18 controls matched for sex, age, comorbidities, and physical activity level with no prior history of SARS-CoV-2 infection were recruited. Subjects were submitted to a maximum-graded cardiopulmonary exercise test (CPX) with an initial 3-min period of a constant, moderate-intensity walk (i.e., below ventilatory threshold, VT). V̇o2 kinetics was remarkably impaired in COVID-19 survivors as evidenced at the on-transient by an 85% (P = 0.008) and 28% (P = 0.001) greater oxygen deficit and mean response time (MRT), respectively. Furthermore, COVID-19 survivors showed an 11% longer (P = 0.046) half-time of recovery of V̇o2 (T1/2V̇o2) at the off-transient. CPX also revealed cardiopulmonary impairments following COVID-19. Peak oxygen uptake (V̇o2peak), percent-predicted V̇o2peak, and V̇o2 at the ventilatory threshold (V̇o2VT) were reduced by 17%, 17%, and 12% in COVID-19 survivors, respectively (all P < 0.05). None of the ventilatory parameters differed between groups (all P > 0.05). In addition, COVID-19 survivors also presented with blunted chronotropic responses (i.e., chronotropic index, maximum heart rate, and heart rate recovery; all P < 0.05). These findings suggest that COVID-19 negatively affects central (chronotropic) and peripheral (metabolic) factors that impair the rate at which V̇o2 is adjusted to changes in energy demands.NEW & NOTEWORTHY Our findings provide novel data regarding the impact of COVID-19 on submaximal and maximal cardiopulmonary responses to exercise. We showed that V̇o2 kinetics is significantly impaired at both the onset (on-transient) and the recovery phase (off-transient) of exercise in these patients. Furthermore, our results suggest that survivors of severe COVID-19 may have a higher metabolic demand at a walking pace. These findings may partly explain the exertional intolerance frequently observed following COVID-19.


Blockade of calcineurin reverses cardiac hypertrophy and induces the down-regulation of JNK mRNA expression in renovascular hypertensive rats.
Recently, calcineurin has been shown to induce cardiac hypertrophy. Mitogen-activated protein kinases (MAPK), including the extracellular-signal regulated kinases (ERK), the c-Jun NH2-terminal kinases (JNK) and the p38 MAPK (p38), have also been shown to be important in the transduction of trophic signals. The objective of this study was to investigate possible cross-talk between calcineurin and MAPK pathways in controlling renovascular hypertension-induced cardiac hypertrophy. Renovascular hypertension was induced by the two kidney-one clip method. The left ventricular weight (LVW) and the ratio of LVW to tibial length were measured to assay the degree of cardiac hypertrophy. Calcineurin activity and MAPK mRNA expression were measured. In the left ventricle of rats with renovascular hypertension, calcineurin activity and JNK mRNA expression were increased while cardiac hypertrophy developed. Treatment with the calcineurin blocker ciclosporin A induced calcineurin inhibition and regression of cardiac hypertrophy with an improvement of cardiac diastolic function. The treatment also resulted in down-regulation of JNK mRNA expression, but the mRNA expressions of ERK and p38 were unchanged. There is cross-talk between the calcineurin and JNK pathway in controlling renovascular hypertension-induced cardiac hypertrophy. Inhibition of the calcineurin and JNK pathways may be the basis of reversal of cardiac hypertrophy by calcineurin blockers.


Conversion of Land Use from Upland to Paddy Field Changes Soil Bacterial Community Structure in Mollisols of Northeast China.
Mollisols are extremely important soil resource for crop and forage production. In northeast China, it is a major land use management practice from dry land crops to irrigated rice. However, there is few data regarding soil quality and microbial composition in Mollisols during land use transition. Here, we analyzed the upper 30 cm of soil from land with more than 30 years of paddy use and from adjacent areas with upland crops. Our results showed that land use and soil depth had a significant effect on soil properties and enzyme activities. Soil moisture (SM) and soil organic carbon (SOC) contents were substantially higher in paddy fields than in upland crop lands, while nitrogen-related enzyme activities were lower. Following the land use change, bacterial diversity was increased and bacterial community composition changed. Taxonomic analyses showed that Proteobacteria, Chloroflexi, Firmicutes, and Bacteroidetes were the dominant phyla present. At family level, Gemmatimonadaceae decreased with land use change, while Syntrophorhabdaceae and Syntrophacea that play a part in methane cycling and nitrifying bacteria such as Nitrospiraceae increased, indicating that the structure and composition of the bacterial community might be a promising indicator of Mollisol health. Redundancy analysis indicated that land use type had a stronger effect on the soil bacterial community composition than soil depth. Additionally, bacterial community composition was closely associated with soil parameters such as soil moisture, pH, SOC, NO3--N, and NH4+-N. Overall, land use change affects the physical and chemical properties of the soil, resulting in changes in the composition of the soil bacterial community and flora. These changes could provide a view of the bacterial community assembly and functional shifts following land use change.