Investigation of the identity of the nucleophile initiating the hydrolysis of phosphate esters catalyzed by dinuclear mimics of metallohydrolases.
di-Zinc(II) complexes of the ligands 2,6-bis((bis(2-methoxyethyl)amino)methyl)-4-methylphenol (HL1), 2,6-bis(bis(hydroxyethyl)aminomethyl)-4-methylphenol (HL2) and 2,6-bis((hydroxyethyl)(methoxyethyl)-aminomethyl)-4-methylphenol (HL3) have been prepared and characterized. The three ligands differ in their donor types, having ether donors (HL1), alkoxido donors (HL2) and both ether and alkoxido donors (HL3). These differences allowed an investigation into the role of the potential nucleophiles in the hydrolysis reaction with the phosphodiester substrate bis(2,4-dinitrophenyl)phosphate (BDNPP). In addition, the di-Mg(II) complex of ligand HL2 was prepared in order to examine the potential for Mg(II) to replace Zn(II) in these biomimetic systems. Kinetically relevant pKa values for the three di-Zn(II) complexes were determined to be 7.14 and 9.21 for [Zn2(L1)(CH3COO)2](PF6), 7.90 and 10.21 for [Zn2(L2)(CH3COO)2](BPh4) and 8.43 and 10.69 for [Zn2(L3)(CH3COO)2](BPh4). At the respective pH optima the relevant catalytic parameters are kcat=5.44(0.11)×10-5s-1 (Km=5.13(0.92) mM), 2.60(0.87)×10-4s-1 (Km=5.49(1.51) mM) and 1.53(0.27)×10-4s-1 (Km=2.14(0.50) mM) for [Zn2(L1)(CH3COO)2](PF6), [Zn2(L2)(CH3COO)2](BPh4) or [Zn2(L3)(CH3COO)2](BPh4), respectively. The di-Mg(II) complex was found to be unreactive in the hydrolysis reaction with BDNPP under the conditions employed. Computational methods using the [Zn2(L2)(CH3COO)2](BPh4) complex were used to discriminate between different possible mechanistic pathways. The DFT calculations indicate that an alkoxido-mediated pathway in the complexes formed with ligands L2 or L3 is unlikely, because it induces significant distortion of the Zn2(L) unit; a direct attack by a coordinated hydroxide is preferred in each of the three systems studied here. The calculations also revealed the important role of ligand structural rigidity.


A modified method for estimation of chemical oxygen demand for samples having high suspended solids.
Determination of chemical oxygen demand (COD) of samples having high suspended solids concentration such as cattle dung slurry with open reflux method of APHA-AWWA-WPCF did not give consistent results. This study presents a modification of the open reflux method (APHA-AWWA-WPCF) to make it suitable for samples with high percentage of suspended solids. The new method is based on a different technique of sample preparation, modified quantities of reagents and higher reflux time as compared to the existing open reflux method. For samples having solids contents of 14.0 g/l or higher, the modified method was found to give higher value of COD with much higher consistency and accuracy as compared to the existing open reflux method.


Recombinant protein expression in the baculovirus-infected insect cell system.
Over the last two decades, the use of eukaryotic cells for expression of recombinant proteins has become the preferred choice for many applications. This is primarily the case when posttranslational modifications and correct disulfide-bond formation are necessary for protein folding and activity. Among the eukaryotic expression systems, the baculovirus-infected insect cell platform has gained particular attention, resulting in the development and implementation of multiple strategies for protein expression. Here, we present baculovirus-infected insect cells as an efficient expression system for eukaryotic proteins. We demonstrate a simplified and a shortened procedure for recombinant virus production that is sufficient for large-scale production of proteins in insect cells.


Pelvic venous variations in patients with congenital inferior vena cava anomalies: classification with computed tomography.
Pelvic venous variations of congenital inferior vena cava (IVC) anomalies that have the potential to cause problems during related surgery and interventional radiology are not fully appreciated. To classify pelvic venous variations of congenital IVC anomalies using computed tomography (CT). CT images for 36 patients with congenital IVC anomalies were retrospectively reviewed. Pelvic venous variations were classified with regard to the relationship with the iliac veins and the presence of interiliac communication. Pelvic venous variations were classified into eight types. One azygous continuation displayed normal connection with the bilateral common iliac veins (CIV) (type 1). Of 28 double IVCs, 11 (39.3%) displayed no interiliac communication (type 2a), five (17.9%) displayed interiliac communication from the left CIV (type 2b), one (3.6%) had communication from the right CIV (type 2c), six (21.4%) had communication from the left internal iliac vein (IIV) (type 2d), and five (17.9%) had communication from the right IIV (type 2e). Six left IVCs displayed symmetrical-to-normal connection with the bilateral CIV (type 3). One absence of infrarenal IVC displayed no connection with the CIV (type 4). Eight types of pelvic venous variations of congenital IVC anomalies were classified using CT.


Novel epitope evoking CD138 antigen-specific cytotoxic T lymphocytes targeting multiple myeloma and other plasma cell disorders.
The development of an immunotherapeutic strategy targeting CD138 antigen could potentially represent a new treatment option for multiple myeloma (MM). This study evaluated the immune function of CD138 peptide-specific cytotoxic T lymphocytes (CTL), generated ex vivo using an HLA-A2-specific CD138 epitope against MM cells. A novel immunogenic HLA-A2-specific CD138(260-268) (GLVGLIFAV) peptide was identified from the full-length protein sequence of the CD138 antigen, which induced CTL specific to primary CD138(+) MM cells. The peptide-induced CD138-CTL contained a high percentage of CD8(+) activated/memory T cells with a low percentage of CD4(+) T cell and naive CD8(+) T cell subsets. The CTL displayed HLA-A2-restricted and CD138 antigen-specific cytotoxicity against MM cell lines. In addition, CD138-CTL demonstrated increased degranulation, proliferation and γ-interferon secretion to HLA-A2(+) /CD138(+) myeloma cells, but not HLA-A2(-) /CD138(+) or HLA-A2(+) /CD138(-) cells. The immune functional properties of the CD138-CTL were also demonstrated using primary HLA-A2(+) /CD138(+) cells isolated from myeloma patients. In conclusion, a novel immunogenic CD138(260-268) (GLVGLIFAV) peptide can induce antigen-specific CTL, which might be useful for the treatment of MM patients with peptide-based vaccine or cellular immunotherapy strategies.


Palladium-catalyzed intramolecular Heck dearomative gem-difluorovinylation of indoles.
A palladium-catalyzed dearomative reaction of indoles has been developed through a domino Heck/gem-difluorovinylation sequence. By taking advantage of a difluorocarbene precursor (ClCF2COONa), the palladium difluorocarbene ([Pd][double bond, length as m-dash]CF2) species was formed smoothly. Then, a migratory insertion/β-H elimination process enabled access to polycyclic indolines containing 1,1-difluoroethylene units in acceptable yields with a broad substrate scope, which also showed dearomative gem-difluorovinylation for the first time. Remarkably, the superb diversified transformations allowed the product to install various functional groups.


Immunohistochemical demonstration of multiple neurohormonal polypeptides in a case of pure testicular carcinoid.
A primary pure testicular carcinoid from a 48-year-old man was examined with antisera raised against various neurohormonal polypeptides. Histochemically, both argyrophil and argentaffin reactions were positive. The immunohistochemical finding of immunoreactive cells for 5-hydroxytryptamine (5-HT) (serotonin), substance P, and vasoactive intestinal polypeptide (VIP) demonstrated the multihormonal nature of this tumor.


Surgical alternatives in ipsilateral recurrence of bronchogenic carcinoma.
In our unit, 5847 patients had pulmonary resections for bronchogenic cancer. Among them, 30 patients suffering from ipsilateral recurrence were operated upon. Recurrence because of incomplete first resection was found most frequently. Operations on ipsilateral recurrent tumours involve a high mortality. However, secondary resection of a recurrent bronchogenic carcinoma may sometimes be a suitable step towards achieving an appreciable survival.


The effect of lead on the avian auditory brainstem.
Lead (Pb) continues to be a significant environmental toxin and remains an integral part of many industrial processes, hobbies, and tobacco smoke. Pb has been shown to be a potent toxin to the CNS and low levels of Pb (below the CDC established toxic blood level of 10 microg/dl) have been correlated with decreases in the IQ of children. Pb exposure is a risk factor for dyslexia, and significantly, dyslexics have deficits in auditory temporal processing, including backward masking and amplitude modulation detection. Importantly, Pb-exposed children have been found to be deficient in various aspects of auditory temporal processing, including backward masking. Auditory temporal information is vital for appropriate speech detection and it is not known where within the auditory axis temporal processing takes place, nor is it understood how Pb exposure modifies the cells of the auditory system. To address these questions, we have developed an animal model of auditory temporal processing using chickens and have established that Pb exposure during development results in deficits in backward masking in avians. The current study was undertaken to identify the cellular changes induced by Pb exposure in the auditory brainstem of chickens that are likely anatomical correlates of the observed deficits in backward masking. We found Pb exposure had no effect on neuron number or glial cells within the auditory brainstem. However, Pb exposure does result in significant decreases in the amount of the medium weight neurofilament protein (NFM) as well as decreased NFM phosphorylation within the axons connecting auditory nuclei in the avian brainstem. Because the amount of neurofilament can affect the conduction velocities of axons, these results may provide an anatomical link between Pb exposure, auditory temporal processing deficits, and dyslexia.


Large-scale demonstration of machine learning for the detection of volcanic deformation in Sentinel-1 satellite imagery.
Radar (SAR) satellites systematically acquire imagery that can be used for volcano monitoring, characterising magmatic systems and potentially forecasting eruptions on a global scale. However, exploiting the large dataset is limited by the need for manual inspection, meaning timely dissemination of information is challenging. Here we automatically process ~ 600,000 images of > 1000 volcanoes acquired by the Sentinel-1 satellite in a 5-year period (2015-2020) and use the dataset to demonstrate the applicability and limitations of machine learning for detecting deformation signals. Of the 16 volcanoes flagged most often, 5 experienced eruptions, 6 showed slow deformation, 2 had non-volcanic deformation and 3 had atmospheric artefacts. The detection threshold for the whole dataset is 5.9 cm, equivalent to a rate of 1.2 cm/year over the 5-year study period. We then use the large testing dataset to explore the effects of atmospheric conditions, land cover and signal characteristics on detectability and find that the performance of the machine learning algorithm is primarily limited by the quality of the available data, with poor coherence and slow signals being particularly challenging. The expanding dataset of systematically acquired, processed and flagged images will enable the quantitative analysis of volcanic monitoring signals on an unprecedented scale, but tailored processing will be needed for routine monitoring applications. The online version contains supplementary material available at 10.1007/s00445-022-01608-x.


Color and lightness constancy in different perceptual tasks.
Color and lightness constancy with respect to changing illumination was studied with three different perceptual tasks: ranking of colored papers according (1) to their lightness and (2) to their chromatic similarity in photopic, mesopic, and scotopic states of adaptation, and (3) recognition of remembered colored papers after changes of illumination in photopic vision. Constancy was found in the second task, only. Excitations of light receptors and luminance channels were computed to simulate the empirical rank orders. Results of the first task can be predicted with the hypothesis that luminance channels are activated, if lightness is asked for. Sequences arranged with respect to chromatic similarity were found independent of the illuminant spectra, even if the calculated rank orders of cone excitation were changed in the altered illumination.


Enhancement of mitogen response and surface marker analysis of lymphocytes from young and old donors after preliminary incubation in vitro.
We have examined the detailed kinetics of PHA induced proliferation of freshly isolated mononuclear cells from young and old human donors. Our studies confirm that donors over the age of 60 years may have a decreased number of PHA responsive cells and that these cells have a significantly diminished rate of entry into the first cell cycle. Age of the donor does not affect the time at which significant numbers of cells appear in first S-phase, the duration of first S-phase, the doubling time in exponential growth, and thymidine uptake per cell. Cells from young and old donors were also cultured in medium supplemented with pooled human serum for 1 or 2 days prior to the PHA response assay. After 2 days of preliminary culture, the PHA response in both young and old is significantly enhanced, with a greater enhancement in the old. The basis of this enhancement appears to be a significant increase in rate of entry into the first cell cycle. None of the other kinetic parameters were significantly altered. The magnitude of the rate enhancement in old donors' cells eliminated the difference in entry rate between young and old after 2 days of preliminary culture. The same rate enhancing effects were seen in the presence of serum pooled from young or old donors. There is no statistically significant change in the number of responding cells after preliminary culture. We had previously suggested, based on lactate dehydrogenase (LD) subunit ratio and patterns of T cell associated surface markers, that less differentiated subpopulations of T cells exist in elderly donors. After preliminary culture, no significant change was seen in the proportions of cells positive for T3, T4, T8, T10 and Ia surface antigens and the unusual pattern of surface marker distribution was still present on the old donors' cells. It appears that the greater rate enhancement in old donors' cells after preliminary culture may not be due to induced maturation of the possibly less differentiated T cell populations described previously. The results do suggest that these subpopulations may be non-responsive to PHA.


Regulatory T cells: development, function and role in autoimmunity.
The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4(+) T cells. Much focus has been placed on thymically derived CD4(+)CD25(+) regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4(+) lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus.


Peptide-Mediated Tumor Targeting by a Degradable Nano Gene Delivery Vector Based on Pluronic-Modified Polyethylenimine.
Polyethylenimine (PEI) is considered to be a promising non-viral gene delivery vector. To solve the toxicity versus efficacy and tumor-targeting challenges of PEI used as gene delivery vector, we constructed a novel non-viral vector DR5-TAT-modified Pluronic-PEI (Pluronic-PEI-DR5-TAT), which was based on the attachment of low-molecular-weight polyethylenimine (LMW-PEI) to the amphiphilic polymer Pluronic to prepare Pluronic-modified LMW-PEI (Pluronic-PEI). This was then conjugated to a multifunctional peptide containing a cell-penetrating peptide (TAT) and a synthetic peptide that would bind to DR5-a receptor that is overexpressed in cancer cells. The vector showed controlled degradation, favorable DNA condensation and protection performance. The Pluronic-PEI-DR5-TAT/DNA complexes at an N/P ratio of 15:1 were spherical nanoparticles of 122 ± 11.6 nm and a zeta potential of about 22 ± 2.8 mV. In vitro biological characterization results indicated that Pluronic-PEI-DR5-TAT/DNA complexes had a higher specificity for the DR5 receptor and were taken up more efficiently by tumor cells than normal cells, compared to complexes formed with PEI 25 kDa or Pluronic-PEI. Thus, the novel complexes showed much lower cytotoxicity to normal cells and higher gene transfection efficiency in tumor cells than that exhibited by PEI 25 kDa and Pluronic-PEI. In summary, our novel, degradable non-viral tumor-targeting vector is a promising candidate for use in gene therapy.


Large-scale, one-step purification of oxidized and reduced forms of bovine brain S100b protein by HPLC.
A rapid and simple method, using a reverse-phase column in a HPLC system, has been developed to purify high yields of both oxidized and reduced S100b proteins from a bovine brain S100 protein mixture. The final proteins were characterized by amino acid analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and absorbance and fluorescence spectroscopy. Both S100b subtypes appeared highly purified and differed only by their oxidation state: all four cysteinyl sulfhydryl groups were free in reduced S100b protein whereas two of them gave disulfide bridges in oxidized S100b protein. The stability of the oxidation state of the two isolated subtypes suggests that the two forms were not in rapid equilibrium and probably coexisted in vivo.


Correction: Maintenance of divergent lineages of the Rice Blast Fungus Pyricularia oryzae through niche separation, loss of sex and post-mating genetic incompatibilities.
[This corrects the article DOI: 10.1371/journal.ppat.1010687.].


[Effect of chemical sympathectomy on the age dynamics of the heart rate and sensitivity of the heart to adrenaline and acetylcholine].
The guanethidine sympathectomy in 4- and 8-week old white rats increased cardiac sensitivity to acetylcholine. An increase of sensitivity to adrenaline was observed in 8 to 20 weeks of postnatal period. The significance of the changes of extracardiac effects and the cardiac sensitivity to acetylcholine and adrenaline for its chronotropic control in sympathectomized 10-14 week old rats is discussed.


A qualitative study of the impact of the implementation of advanced access in primary healthcare on the working lives of general practice staff.
The North American model of 'advanced access' has been emulated by the National Primary Care Collaborative in the UK as a way of improving patients' access in primary care. The aim of this study was to explore the impact of the implementation of advanced access on the working lives of general practice staff. A qualitative study design, using semi-structured interviews, was conducted with 18 general practice staff: 6 GPs, 6 practice managers and 6 receptionists. Two neighbouring boroughs in southeast England were used as the study sites. NUD*IST computer software assisted in data management to identify concepts, categories and themes of the data. A framework approach was used to analyse the data. Whilst practice managers and receptionists saw advanced access as having a positive effect on their working lives, the responses of general practitioners (GPs) were more ambivalent. Receptionists reported improvements in their working lives with a change in their role from gatekeepers for appointments to providing access to appointments, fewer confrontations with patients, and greater job satisfaction. Practice managers perceived reductions in work stress from fewer patient complaints, better use of time, and greater flexibility for contingency planning. GPs recognised benefits in terms of improved consultations, but had concerns about the impact on workload and continuity of care. AA has improved working conditions for receptionists, converting their perceived role from gatekeeper to access facilitator, and for practice managers as patients were more satisfied. GP responses were more ambivalent, as they experienced both positive and negative effects.


The relationship between cough-specific quality of life and abdominal muscle endurance, fatigue, and depression in patients with COPD.
Cough is a prevalent symptom that impacts quality of life in COPD. The aim of this study was to assess the relationship between cough-specific quality of life, abdominal muscle endurance, fatigue, and depression in stable patients with COPD. Twenty-eight patients with COPD (mean age 60.6±8.7 years) referred for pulmonary rehabilitation participated in this cross-sectional study. Sit-ups test was used for assessing abdominal muscle endurance. Leicester Cough Questionnaire (LCQ) was used to evaluate symptom-specific quality of life. Fatigue perception was evaluated with Fatigue Impact Scale (FIS). Beck Depression Inventory (BDI) was used for assessing depression level. The LCQ total score was significantly associated with number of sit-ups; BDI score; FIS total; physical, cognitive, and psychosocial scores (P<0.05). Scores of the LCQ physical, social, and psychological domains were also significantly related with number of sit-ups, FIS total score, and BDI score (P<0.05). FIS total score and number of sit-ups explained 58% of the variance in LCQ total score (r=0.76, r (2)=0.577, F(2-20)=12.296, P<0.001). Chronic cough may adversely affect performance in daily life due to its negative effect on fatigue and decrease abdominal muscle endurance in patients with COPD. Decreased cough-related quality of life is related with increased level of depression in COPD patients. Effects of increased abdominal muscle endurance and decreased fatigue in COPD patients with chronic cough need further investigation.


Graphitic carbon nitride as high-resolution stationary phase for gas chromatographic separations.
This work presents the first example of utilization of graphitic carbon nitride (g-C3N4) as stationary phase for capillary gas chromatographic (GC) separations. The statically coated g-C3N4 column showed the column efficiencies of 3760 plates/m and weak polarity. Its resolving capability and retention behaviours were investigated by using the Grob test mixture, and mixtures of diverse types of analytes, and structural and positional isomers. The results showed superior separation performance of the g-C3N4 stationary phase for some critical analytes and preferential retention for aromatic analytes. Specifically, it exhibited high-resolution capability for aromatic and aliphatic isomers such as methylnaphthalenes and dimethylnaphthalenes, phenanthrene and anthracene and alkane isomers. In addition, g-C3N4 column showed excellent thermal stability up to 280°C and good repeatability with relative standard deviation (RSD) values less than 0.09% for intra-day, below 0.23% for inter-day and in the range of 1.9-8.4% for between-column, respectively. The advantageous separation performance shows the potential of g-C3N4 and related materials as stationary phase in GC and other separation technologies.


The spatial changes of China's environmental efficiency and driving factors from the perspective of circular economy.
This paper mainly uses the super-efficiency EBM model to measure the environmental efficiency of 30 provinces in China from 2005 to 2019, utilizes the Theil index to analyze the degree of differentiation, and investigate the stochastic convergence of environmental efficiency in different regions. At the same time, it focuses on exploring the direction, intensity, and changing trend of the internal driving factors of environmental efficiency including fiscal decentralization and tax competition, so as to measure and show the overall situation of circular economy development. The research results show that (1) from a national perspective, environmental efficiency shows a pattern of gradual convergence from east to west and from coast to inland. There is a significant stepped regional imbalance in the development level of circular economy in the eastern coastal areas and the central, western inland areas. (2) The differences in environmental efficiency among the four major economic regions were apparently significant while the differences inside each region itself were relatively minor, although in a trend of being gradually widened. There are differences in the development level of circular economy in different regions or within the same region. (3) The inter-provincial efficiency in the eastern, western and northeastern zones maintained relatively stable, while the inter-provincial differences in the central region were expanding. The environmental deficit problem caused by economic development has been alleviated and the basic development model of circular economy has been initially established. (4) Economic development has played a positive role in improving the environmental efficiency of the region. But the resident consumption level inhibited the improvement of the environmental efficiency level of the surrounding areas. The conclusion of this paper can provide a macroscopic reference for the government in finding effective countermeasures to improve environmental efficiency.


The miR-455-5p/ERα36 axis regulates mammalian neuronal viability and axonal regeneration.
Estrogen signal transduction plays an important role in regulating neuronal cell growth and axonal regeneration. Estrogen receptor alpha 36 (ERα36) is a truncated isoform of the estrogen receptor that inhibits aspects of estrogen transduction. Here, we investigated the role of ERα36 in neuronal viability as well as axonal growth and regeneration using SH-SY5Y neuroblastoma cells and murine sensory neurons. We identified an ERα36-targeting microRNA, miR-455-5p, that negatively regulates ERα36 levels. miR-455-5p inhibition increased cell viability, PCNA, cyclin D1, and Bcl-2 levels and decreased apoptosis and Bax levels in SH-SY5Y neuroblastoma cells. Moreover, miR-455-5p inhibition upregulated the phosphorylation of the intracellular signaling mediators MEK, ERK, Akt, and mTOR in SH-SY5Y neuroblastoma cells. miR-455-5p inhibition promoted axonal growth and regeneration and downregulated activation of the glycogen synthase kinase-3β (GSK3β)/Tau protein pathway in murine sensory neurons. ERα36 silencing was sufficient to reverse the phenotypic characteristics produced by miR-455-5p inhibition, suggesting that ERα36 is mechanistically linked to miR-455-5p. We provide additional mechanistic evidence showing that GSK3β is the mediator of miR-455-5p/ERα36-induced axonal growth. Together, these findings elucidate a novel miR-455-5p/ERα36 axis that regulates mammalian neuronal viability and axonal regeneration.


Percutaneous catheter drainage of obstructed transplant kidney in pregnancy.
Obstruction of a transplanted kidney may occur during pregnancy and necessitate early cesarean section, with considerable risk to the immature fetus. We report a case where percutaneous catheter nephrostomy relieved the obstruction and allowed the pregnancy to progress until the fetus was mature.


Do Patients Benefit From a Cochlear Implant When They Qualify Only in the Presence of Background Noise?
To compare the difference in pre- to postoperative speech performance of patients qualifying for a cochlear implant (CI) in quiet, +10 dB signal-to-noise ratio (SNR), and +5 dB SNR. Retrospective. Tertiary referral center. Fifty-eight post-lingually deafened, unilateral CI recipients from three Groups were included: 1) those who met CI candidacy criteria with AzBio sentences in quiet, 2) in noise at +10 dB SNR but not in quiet, 3) and in noise at +5 dB SNR but not in quiet or +10 dB SNR. Unilateral CI. Pre- and 1 year postoperative speech recognition scores. Best-aided AzBio speech recognition of individuals in Group 1 improved significantly for all test conditions and improved significantly for Groups 2 and 3 in the +10 and +5 dB SNR test conditions postoperatively. When tested with their CI alone however, while AzBio speech recognition of individuals in Group 1 and Group 2 improved significantly in the quiet and +10 dB SNR conditions, speech recognition was not significantly changed postoperatively under any testing condition for individuals in Group 3. While individuals qualifying for a CI only in the +5 dB SNR condition may derive significant benefit from implantation in best aided conditions, speech understanding outcomes can be more variable thus warranting additional counseling before implantation and case-by-case consideration of listening needs and goals.


Hypertension, its correlates and differences in access to healthcare services by gender among rural Zambian residents: a cross-sectional study.
To examine the prevalence of hypertension and access to related healthcare services among rural residents of Mumbwa district in Zambia. Cross-sectional study with probability cluster sampling. Rural Zambia. We recruited 690 residents from Mumbwa district aged 25-64 years who had been living in the study area for ≥6 months and had adopted the lifestyle of the study area. Pregnant women and women who had given birth in the past 6 months were excluded. The data collection-questionnaire survey and anthropometric and biological measurements-was conducted between May and July 2016. In the overall sample, 39.7% and 33.5% of the men and women had hypertension (systolic blood pressure (BP)≥140 or diastolic BP ≥90 mm Hg), respectively. Among the participants without a previous diagnosis of hypertension, 30.3% presented with hypertension at the time of measurement. In the multivariable analysis, alcohol intake and urban residence in men, and older age group, higher education and body mass index ≥25 kg/m2 in women were significantly associated with hypertension. Among the 21.8% who never had their BP measured, 83.8% were men; among these men, older age (adjusted OR (AOR), 0.43; 95% CI 0.25 to 0.73) and HIV positive status (AOR, 0.37; 95% CI 0.14 to 0.97) were negatively associated, while current smoker status (AOR, 2.09; 95% CI 1.19 to 3.66) was positively associated with the lack of BP measurements. We found that hypertension is prevalent in the target rural area. However, many were not aware of their hypertension status and many never had their BP measured, indicating a serious gap in cardiovascular disease prevention services in Zambia. There is an urgent need for health promotion and screening for hypertension, especially in the primary health services of rural Zambia. Issues related to healthcare accessibility in men require particular attention.


Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C.
In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2-4 as "possible" MD. Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06-25.92] for FGF21 and 3.5 (95%CI: 1.19-10.25) for GDF15. Relationships persisted after covariate adjustments. FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.


Prognostic Value of Fluorine-19 MRI Oximetry Monitoring in cancer.
Hypoxia is a key prognostic indicator in most solid tumors, as it is correlated to tumor angiogenesis, metastasis, recurrence, and response to therapy. Accurate measurement and mapping of tumor oxygenation profile and changes upon intervention could facilitate disease progression assessment and assist in treatment planning. Currently, no gold standard exists for non-invasive spatiotemporal measurement of hypoxia. Magnetic resonance imaging (MRI) represents an attractive option as it is a clinically available and non-ionizing imaging modality. Specifically, perfluorocarbon (PFC) beacons can be externally introduced into the tumor tissue and the linear dependence of their spin-lattice relaxation rate (R1) on the local partial pressure of oxygen (pO2) exploited for real-time tissue oxygenation monitoring in vivo. In this review, we will focus on early studies and recent developments of fluorine-19 MRI and spectroscopy (MRS) for evaluation of tumor oximetry and response to therapy.


Differential effect of cholera toxin on CD45RA+ and CD45RO+ T cells: specific inhibition of cytokine production but not proliferation of human naive T cells.
We have studied how cholera toxin (CT) and its non-toxic cell-binding B-subunit (CTB) affect the activation of pure human T cells in an anti-CD3-driven system. CT, as opposed to CTB, strongly suppressed the proliferative responses as well as cytokine production in CD4+ and CD8+ T cells. CT however, had a differential effect on naive and activated/memory T cell subsets. Costimulation through exogenous IL-2 or through CD28 cross-linking rescued the proliferation of CT-treated naive CD45RA+ T cells, but not of activated/memory CD45RO+ cells. IL-2 production and IL-2 receptor expression were markedly reduced by CT in all T cell fractions, i.e. also in CD45RA+ cells which had maintained proliferative responses. However, the proliferative responses of CT-treated CD45RA+ T cells were IL-2-dependent, as shown by blocking experiments using anti-IL-2 antibodies. These results indicate (i) that CTB has no cytostatic effect on human T cells, (ii) that CT affects proliferation and cytokine production by two different signal pathways, and (iii) that CT might interact with a signal pathway generated through or influenced by CD45.


The effect of H-2IJ disparity on induction of allotransplantation tolerance by lentil lectin.
The effect of an H-2IJ disparity on skin graft survival was studied in 18 mouse donor-recipient strain combinations, in which the recipients were treated with an efficient immunosuppressant, lentil lectin (LCA). The simultaneous I-J disparity essentially had no (or a slightly adverse) effect on the graft survival times in strain combinations differing at the K and I-A loci or in the entire H-2 complex. In two strain combinations incompatible at the D locus, the simultaneous I-J disparity promoted graft survival. The disparity at the I-J locus therefore seems to have only a marginal effect on the survival of allografts in most of the LCA-treated recipients, but it may promote graft survival in some animals. A similar tolerance-promoting effect was also observed with D disparity.


ISO 10993 biological evaluation of novel hemostatic powder - 4SEAL®.
Hemostasis plays a crucial role during every surgery allowing for a bloodless operating field. Fast and effective surgery leads to a reduced risk of postoperative complications. One of the latest methods for achieving homeostasis is using natural polysaccharide-based hemostatic powders. The study aimed to evaluate the biocompatibility according to the ISO 10993 standards of 4SEAL® Hemostatic powder. Chemical characterization (Headspace GC-MS, GC-MS, and ICP-MS), cytotoxicity, genotoxicity (MLA and AMES), endotoxin contamination, sensitization potential, intracutaneous reactivity, acute and subacute systemic toxicity with implantation, and pyrogenicity were evaluated to investigate the biocompatibility of the 4SEAL® Hemostatic powder. Studies were conducted according to ISO 10993 standards. The biocompatibility requirements according to ISO 10993-1 for 4SEAL® Hemostatic powder were met. Based on the conducted in-vitro studies, 4SEAL® Hemostatic powder shows a non-cytotoxicity and non-mutagenic potential. Also, the results of in vivo studies of 4SEAL® Hemostatic powder shows no signs of toxicity, non-sensitizing, non-irritating, and no pyrogenicity potential. In the chemical characterization of 4Seal® Hemostatic Powder, no compounds were identified above Analytical Evaluation Threshold (AET) and no elements with concentrations higher than element-specific PDE [μg/day] were detected. 4SEAL® Hemostatic powder is a promising new hemostatic agent with a wide range of potential applications and excellent biocompatibility.


Skin Cancer-Associated S. aureus Strains Can Induce DNA Damage in Human Keratinocytes by Downregulating DNA Repair and Promoting Oxidative Stress.
Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can have cancer-promoting effects on skin cells, we performed RNA sequencing and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant ('secretome') from four S. aureus clinical strains isolated from AK and SCC. Secretomes of two of the S. aureus strains induced keratinocytes to overexpress biomarkers associated with skin carcinogenesis and upregulated the expression of enzymes linked to reduced skin barrier function. Further, these strains induced oxidative stress markers and all secretomes downregulated DNA repair mechanisms. Subsequent experiments on an expanded set of lesion-associated S. aureus strains confirmed that exposure to their secretomes led to increased oxidative stress and DNA damage in primary human keratinocytes. A significant correlation between the concentration of S. aureus phenol soluble modulin toxins in secretome and the secretome-induced level of oxidative stress and genotoxicity in keratinocytes was observed. Taken together, these data demonstrate that secreted compounds from lesion-associated clinical isolates of S. aureus can have cancer-promoting effects in keratinocytes that may be relevant to skin oncogenesis.


Development of ultrasensitive direct chemiluminescent enzyme immunoassay for determination of aflatoxin B1 in food products.
A direct competitive chemiluminescent enzyme-linked immunosorbent assay (CL-ELISA) for determination of aflatoxin B1 (AFB1) was developed. To improve the assay sensitivity, a mixture of 3-(10'-phenothiazinyl)-propane-1-sulfonate and 4-morpholinopyridine previously optimized by a factorial design was used as enhancer of horseradish peroxidase-induced chemiluminescence. Varying the concentrations of the coating anti-AFB1 antibody and conjugate of AFB1 and horseradish peroxidase the conditions of the chemiluminescent assay were optimized. The values of the detection limit value and dynamic working range of CL-ELISA of AFB1 were 0.0015 ng mL(-1) and 0.003-0.03 ng mL(-1), respectively. It was shown that a dilution of rice and mung beans extracts in 5 and 10 times, respectively, prevented a matrix effect of the food products in CL-ELISA. The recovery values from the spiked samples of rice and mung beans were in the range of 90-104% and 102-117%, respectively. Studying 8 rice and 8 mung beans samples purchased in commercial stores the developed CL-ELISA allowed to find 3 samples (1 rice and 2 mung beans) containing AFB1, the content of AFB1 in one sample being higher than the maximum acceptable level established in the European Community.


Snow mold of winter cereals: a complex disease and a challenge for resistance breeding.
Snow mold resistance is a complex quantitative trait highly affected by environmental conditions during winter that must be addressed by resistance breeding. Snow mold resistance in winter cereals is an important trait for many countries in the Northern Hemisphere. The disease is caused by at least four complexes of soilborne fungi and oomycetes of which Microdochium nivale and M. majus are among the most common pathogens. They have a broad host range covering all winter and spring cereals and can basically affect all plant growth stages and organs. Their attack leads to a low germination rate, and/or pre- and post-emergence death of seedlings after winter and, depending on largely unknown environmental conditions, also to foot rot, leaf blight, and head blight. Resistance in winter wheat and triticale is governed by a multitude of quantitative trait loci (QTL) with mainly additive effects highly affected by genotype × environment interaction. Snow mold resistance interacts with winter hardiness in a complex way leading to a co-localization of resistance QTLs with QTLs/genes for freezing tolerance. In practical breeding, a multistep procedure is necessary with (1) freezing tolerance tests, (2) climate chamber tests for snow mold resistance, and (3) field tests in locations with and without regularly occurring snow cover. In the future, resistance sources should be genetically characterized also in rye by QTL mapping or genome-wide association studies. The development of genomic selection procedures should be prioritized in breeding research.


Pregnancy complicated with aortic dissection: Two cases report.
This study aims to investigate the characteristics of pregnancy complicated with aortic dissection (AD), diagnosis and treatment plan, and maternal and infant outcomes. Two pregnant women suffered persistent back pain were admitted to Hubei Maternal and Child Health Hospital from December 2019 to December 2020. Pregnant women with chest and back pain and especially hypertension should be highly suspected of AD. However, to confirm diagnosis results, laboratory tests such as D-dimer, fibrinogen and white blood cells, and even some Special examination, cardiac ultrasound, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), are required. Early diagnosis and intervention can improve maternal and infant outcomes. Cesarean sections were performed in both patients. Case 1 underwent thoracic aortic stent implantation one day after the onset of AD symptoms. Case 2 received endovascular repair of AD 4 days after the onset of AD symptoms. In these two cases, good maternal and infant outcomes were obtained through effective early identification and treatment. AD is characterized with an acute onset, and the rates of misdiagnosis and missed diagnosis are high, which seriously endangers the life of mother and child. Hypertension is one of the high-risk factors causing AD. Good maternal and infant outcomes can be achieved by early identification, multidisciplinary collaboration and timely cardiac surgical intervention.


Chronic tellurium intoxication in rats.
(1) Accumulation of neuronal lipofuscin was clearly demonstrated in the chronic tellurium intoxication in young rats with histological, fluorescent and electron-microscopical methods; (2) The needle-shaped crystal in the neuronal lysosomes were demostrated to contain the tellurium with electron dispersive spectrophotometry analysis. (3) The vacuolation of the cytoplasm of Schwann cells was the initial pathological change noted in the tellurium peripheral neuropathy.


Uveodermatologic lymphoma in two young related Portuguese water dogs.
Canine lymphoma (CL) is one of the most common forms of spontaneous canine neoplasia. Improved understanding of the genetic and environmental factors associated with CL may provide benefits for the study of non-Hodgkin's and Hodgkin's lymphoma in humans. Uveodermatologic lymphoma is reported in a single household of Portuguese water dog, and the etiology is discussed. A 1-year-old female intact Portuguese water dog was referred to the Ophthalmology Service of the Veterinary Teaching Hospital of the Autonomous University of Barcelona because of acute blepharospasm of the right eye in association with a multinodular dermatosis. Physical and ophthalmological examination and a complete diagnostic work-up, including skin and ocular histopathology and immunohistochemistry, were performed. Three months prior, in Galicia (Spain), 1200 km away from Barcelona, a male dog of the same litter showed very similar oculodermatological clinical signs and skin histopathology, and immunohistochemistry were obtained. The clinical diagnoses were anterior exudative uveitis, iridal masses, and secondary glaucoma. Histopathology and immunohistochemistry revealed a nonepitheliotropic lymphoma rich in B cell in dog 1 and rich in T cell in dog 2. It is proposed that an underlying genetic predisposition could have played a role in the development of lymphoma in these two young related dogs.


Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cisplatin via MAPK/mitochondrial pathway.
Previous reports have implicated epithelial-mesenchymal transition (EMT) as a major cause of cancer. TWIST, a novel zinc finger transcription factor, was suggested to be an important inducer of EMT and therefore be involved in different phases of tumorigenicity. However, whether TWIST suppression could increase chemosensitivity of cancer cells to chemotherapeutic agent remains unclear. In the present study, we utilized RNA interference to knockdown TWIST expression in A549 cells and further assessed the cell viability and apoptosis as well as possible MAPKs and mitochondrial pathways. The data showed that TWIST depletion significantly sensitized A549 cells to cisplatin by inducing activation of JNK/mitochondrial pathway but not ERK and p-38 pathways, suggesting critical roles of TWIST in A549 cell chemoresistance to cisplatin and raising the possibility of TWIST depletion as a promising approach to lung cancer therapy.


Studies on dechlorination of DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) using magnesium/palladium bimetallic system.
The aim of our investigation was to compare the rates of dechlorination of DDT using Mg0/Pd4+ system in two different reaction phases, namely, water-acetone and 0.05% biosurfactant in water. Since palladium is expensive and its toxicity effects are not well known we also examined the reuse efficiency of Pd0 immobilized on alumina for dechlorinating DDT. Studies on the dechlorination of DDT in water-acetone (1:1, v/v) and 0.05% biosurfactant phases revealed that the reaction followed second order kinetics and rate of reaction is dependent upon both initial concentrations of the target compound and Mg0/Pd4+. The presence of acid enhanced the rate of reaction by providing protons and preventing passivation of metal that occurs due to deposition of magnesium hydroxide. GC-MS analyses revealed the formation of completely dechlorinated hydrocarbon skeleton of DDT namely, diphenylethane (DPE), as the end product in both reaction phases (water-acetone and 0.05% biosurfactant in water) thereby implying the removal of all five chlorine atoms (three alkyl and two aryl) of DDT. The optimum ratio of water and acetone to facilitate successful dechlorination reaction was found to be 9:1. Results suggested that salt form (K2PdCl6) of palladium had higher potential to dechlorinate DDT as compared to pellet (Pd0-alumina) form (efficiencies of 95 and 36%, respectively, for 100 ppm initial concentration of DDT). We noted that Pd0-alumina pellets could be reused at least four times for successful dechlorination of DDT provided Mg0 granules are present in sufficient quantity. Technical grade DDT (50 ppm) containing significant amounts of DDD was dechlorinated almost completely by the Mg0/Pd4+ (10mg/0.2mg/ml) within 1h in water-biosurfactant phase. Our studies reveal that Mg/Pd system is a promising option due to its high reactivity and its ability to achieve complete dechlorination of DDT. This bimetallic system may be useful for designing indigenous permeable barriers or reactors for the treatment of DDT contaminated water.


Complete assignments of 1H and 13C NMR data for ten phenylpiperazine derivatives.
Ten phenylpiperazine derivatives were designed and synthesized. The first complete assignments of (1)H and (13)C NMR chemical shifts for these phenylpiperazine derivatives were achieved by means of 1D and 2D NMR techniques, including (1)H-(1)H COSY, HSQC and HMBC spectra.


Efficacy and Safety of Botulinum Toxin Type A Injection in Patients with Bilateral Trapezius Hypertrophy.
To evaluate aesthetic outcomes in patients with bilateral trapezius hypertrophy treated by botulinum toxin type A (BTxA) injection for aesthetic reconstruction of the upper trapezius. From May 2015 to May 2016, 30 women with a short neck shape resulting from bilateral trapezius hypertrophy were treated with botulinum toxin type A (BTxA) injection at the most affected area of the upper trapezius. Pre- and postoperative values of SACDF (irregularly shaped area of the four points A, C, D, and F) and SACDE (irregularly shaped area of the four points A, C, D, and E), responses to patients' and doctors' Global Aesthetic Improvement Scale (GAIS) questionnaires for neck aesthetic assessment, as well as reported adverse events, were recorded and analyzed. Duration of follow-up ranged from 4 to 12 months. Subjects experienced non-severe adverse events and complete recovery after a single BTxA injection. In patients' GAIS questionnaires, "very much improved" accounted for 53%, "much improved" accounted for 13%, and "improved" accounted for 27%. In doctors' GAIS questionnaires, "very much improved" accounted for 27%, "much improved" accounted for 33%, "improved" accounted for 33%, and "no change" accounted for 7%. The overall degree of improvement was high. Statistically significant differences were observed with respect to the "very much improved" response to GAIS questionnaires between patients and doctors (P = 0.035). A single injection of BTxA for aesthetic reconstruction of the upper trapezius is safe and effective in patients with bilateral trapezius hypertrophy. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Dynamic evaluation and prediction of the ecological environment quality of the urban agglomeration on the northern slope of Tianshan Mountains.
In order to timely determine the dynamic changes of the ecological environment quality and future development laws of the urban agglomeration on the northern slope of the Tianshan Mountains, combined with the actual situation of the urban agglomeration, 11 indicators were selected from the three aspects of natural ecology, social ecology, and economic ecology. To reduce the dimensions of the indicators, principal component analysis, coefficient of variation, and analytic hierarchy process were used based on RS and GIS technology methods, and the ecological environmental quality (EQI) from 2000 to 2018 was dynamically evaluated. Further, the CA-Markov model was introduced to simulate the development status in 2026 for predictive purposes. The main results are as follows: the overall ecological environment of the area exhibited a gradually improving distribution change from southwest to northeast; the proportion of ecological environment classification exhibited a gradually decreasing change pattern; the spatial differentiation of ecological environment quality exhibited a significant spatial positive correlation; from the influencing factors, an observation can be made that natural ecological factors were highly significant; the prediction accuracy verification revealed that the CA-Markov model was suitable for the prediction of the ecological environment quality in the region and had high accuracy; and the comprehensive regional ecological environment quality indexes were 5.7392, 6.1856, and 6.4366, respectively, while the forecasted value for 2026 was predicted to be 6.6285, indicating that the overall ecological environment quality of the region will improve and develop well. The present research results reveal the law of dynamic changes and future development of the ecological environment quality in the region, which can be used as a theoretical reference for the formulation of ecological environmental protection measures.


Resveratrol compares with melatonin in improving in vitro porcine oocyte maturation under heat stress.
Resveratrol, an important phyto-antioxidant commonly found in grapes, mulberry, and other plants, has a variety of functions including anti-aging, anti-cancer and anti-inflammatory activities. In the current study, we investigated the beneficial effects of resveratrol on in vitro porcine oocyte maturation under heat stress (HS). The effect of resveratrol, melatonin and their combination on alleviating HS was compared according to the maturation rate of oocytes and the development competence of embryos after parthenogenetic activation (PA). Supplementation with resveratrol (2.0 μmol/L) not only improved the nuclear maturation but also raised the blastocyst rate of porcine embryos' PA from oocytes that underwent HS by increasing their glutathione (GSH) level, reducing reactive oxygen species (ROS) and up-regulating the expression of Sirtuin 1 (SIRT1). It was also found that melatonin (10(-7) mol/L) and the combination of resveratrol (2.0 μmol/L) plus melatonin (10(-7) mol/L) exhibited more potent effects than resveratrol alone regarding their protective activities on oocyte maturation under HS. This study compared the efficiencies of resveratrol, melatonin and their combination for protecting porcine oocytes from heat stress. The mechanisms are attributed to the fact that each treatment may have different ability to regulate the synthesis of steroid hormones and the expression of mature related genes.


MRI evaluation of tuberous sclerosis.
The authors present four cases of tuberous sclerosis examined with MRI. The patho-anatomic aspects are reviewed and analysed with respect to MRI data. MRI appears superior to the CT particularly for imaging of cortical tubers, cystic lesions, and heterotopic clusters; these last two features were never described with MRI before. Here is also presented the second progressive case of giant intracranial aneurysm associated with tuberous sclerosis.


Iodide mumps.
Iodide sialadenitis is a rare, delayed idiosyncratic reaction to iodine-containing contrast media. We present non-contrast computed tomography images of this benign but dramatic adverse reaction occurring in the submandibular glands.


A functional polymorphism in the ATP-Binding Cassette B1 transporter predicts pharmacologic response to combination of nortriptyline and morphine in neuropathic pain patients.
Many genetic markers have been associated with variations in treatment response to analgesics, but none have been assessed in the context of combination therapies. In this study, the treatment effects of nortriptyline and morphine were tested for an association with genetic markers relevant to pain pathways. Treatment effects were determined for single and combination therapies. A total of 24 functional single nucleotide polymorphisms were tested within the gene loci of mu-opioid receptor (OPRM1) gene locus, ATP-Binding Cassette B1 Transporter (ABCB1), Cytochrome P450 gene family (CYP2C19 and CYP2D6), catecholamine inactivator Catechol-O-Methyl Transferase (COMT), and serotonin receptor 2A (HTR2A). Genotyping was performed in a population of neuropathic pain patients who previously participated in a clinical trial. For monotherapy, neither nortriptyline nor morphine responses were associated with single nucleotide polymorphisms. However, for nortriptyline + morphine combination therapy, the single nucleotide polymorphism rs1045642 within the drug efflux pump ABCB1 transporter significantly predicted analgesic response. The presence of the C allele accounted for 51% of pain variance in this subgroup in response to combination treatment. The T-allele homozygotes demonstrated only 20% improvement in pain scores, whereas the C-allele homozygotes 88%. There was no significant contribution of rs1045642 to the medication side effects under all treatment conditions. The UK Biobank data set was then used to validate this genetic association. Here, patients receiving similar combination therapy (opioid + tricyclic antidepressant) carrying the C allele of rs1045642 displayed 33% fewer body pain sites than patients without that allele, suggesting better pain control. In all, our results show a robust effect of the rs1045642 polymorphism in response to chronic pain treatment with a nortriptyline + morphine combination.


Neuroprotective Effects of Milrinone on Acute Traumatic Brain Injury.
Traumatic brain injury is still an important health problem worldwide. Traumatic brain injury not only causes direct mechanical damage to the brain but also induces biochemical changes that lead to secondary nerve cell loss. In this study, we investigated the neuroprotective effect of milrinone after traumatic brain injury (TBI) in a rat model. Forty male Wistar albino rats, were used. Rats were divided into 4 groups: 1) sham, 2) TBI, 3) TBI + Ringers, and 4) TBI + Milrinone. In group 1 (sham), only craniotomy was performed. In group 2 (TBI), TBI was performed after craniotomy. In group 3 (TBI + Ringer), TBI was performed after craniotomy and intraperitoneal Ringers solution was given immediately afterward. Group 4 (TBI + Milrinone), TBI was performed after craniotomy, and milrinone was given 1.0 mg/kg milrinone intraperitoneally directly (0.5 mg/kg milrinone intraperitoneally again 24 hours, 48 hours, and 72 hours after trauma). Tests were performed for neurological and neurobehavioral functions. Immunohistochemistry and histopathology studies were performed. In group 4 compared with group 2 and group 3 groups, tests for neurological functions and neurobehavioral functions were significantly better. In the milrinone treatment used in group 4, plasma and brain tissue tumor necrosis factor, 8-OH 2-deoxyguanosine , and interleukin 6 levels were significantly decreased, and increased plasma and tissue IL-10 levels were detected. Histopathological spinal cord injury and apoptotic index increased in groups 2 and 3, while significantly decreasing in group 4. This study shows for the first time that the anti-inflammatory, antioxidant and antiapoptotic properties of milrinone may be neuroprotective after TBI.


Chronic obstructive pulmonary disease diagnosis: the simpler the better? Not always.
The acronym chronic obstructive pulmonary disease (COPD) has been introduced in the early 1960s to describe a disease characterized by largely irreversible airflow obstruction, due to a combination of airway disease and pulmonary emphysema, without defining their respective contribution to the pathology. COPD is a disorder that causes considerable morbidity and mortality. Currently, it represents the fourth leading cause of death in the world, and it is expected to increase both in prevalence and in mortality over the next decades. The most widely adopted definition of COPD is that of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), that recommends the use of the post-bronchodilator forced expiratory volume in the first second to forced vital capacity ratio (FEV1/FVC)<0.7 to define irreversible airflow obstruction. This approach, called "fixed ratio", has been introduced to provide a simple tool for COPD diagnosis, as it is easy to remember. Even if modern medicine and research seem to prefer rigid cut-offs and classifications, this often contrasts with the complex nature of the disease. The aim of the present review is to explain that such a fixed cut-off failed to increase COPD diagnosis, and furthermore often leads to inescapable misclassification of patients, with the risk of an excessive simplification of a clinical approach necessarily complex.


Prognostic significance of residual nodal disease after neoadjuvant endocrine therapy for hormone receptor-positive breast cancer.
Axillary management after NET has not been well studied and the significance of residual axillary node disease after NET remains uncertain. We used the National Cancer Data Base to examine the prognostic significance of residual nodal disease after NET. From 2010-2016, 4,496 patients received NET for cT1-3N0-1M0 hormone receptor-positive, HER2-negative breast cancer. Among cN0 patients treated with NET, final node status was ypN0 in 65%, isolated tumor cells (ITCs) in 3%, ypN1mi in 6%, and ypN1 in 26%. In cN1 patients, nodal pathologic complete response was uncommon (10%), and residual nodal disease included ITCs in 1%, ypN1mi in 3%, and ypN1 in 86%. There were no differences in 5-year overall survival (OS) between patients with pathologic node-negative disease, ITCs, or micrometastases after NET. When compared to a matched cohort of upfront surgery patients, there were also no differences in 5-year OS between NET and upfront surgery patients for any residual nodal disease category. These findings suggest NET patient outcomes mirror those of upfront surgery patients and present an opportunity to consider de-escalation of axillary management strategies in NET patients.


Chronic pain and discomfort after inguinal hernia repair.
The purpose of this study was to estimate the incidence and degree of persistent chronic pain after inguinal hernia repair performed in our hospitals. We mailed a questionnaire on the frequency and intensity of postoperative inguinal pain and discomfort to 219 adult patients who had undergone inguinal hernia repair in one of our hospitals more than 3 months previously. There were 191 (87.2%) respondents, 28 (14.7%) of whom reported pain and 33 (17.3%) reported discomfort. The frequency of pain was "rare" in more than half of the patients who reported pain. No patient reported "continuous" pain. The intensity of the pain was "mild" in most of the patients, and none reported "pain that required a painkiller". The answers on the face scale questionnaire (score "0" to "10") were "0" or "1" for most of the patients. The incidence of chronic pain and/or discomfort was significantly higher in women than in men, and tended to be higher in patients who had undergone repair using onlay mesh. The frequency and intensity of persistent chronic pain or discomfort after inguinal hernia repair was not high or severe. These data will be useful for further studies to determine the best treatment for adult inguinal hernia.


[Dynamic change of androgen-receptor in tumor and surrounding liver tissue of nude mice model with transplanted human HCC].
To research into the law of androgen-receptor (AR) dynamic change in developing course of human HCC. Dynamic measurement of AR in tumor and peritumorous tissue was performed in nude mice model with orthotopic transplanted human HCC. Tumor nodules were present in 90% nude mice 4 weeks after transplantation, tumor necrosis was found in the 10th week, and remarkable necrosis occurred in the 12th week. The quantity of AR in tumor and peritumorous tissue was highest in the early stage of tumor (102.32 +/- 21.42 fmol/mg protein and 72.45 +/- 10.11 fmol/mg protein respectively), and then decreased progressively with time to the 10th week (40.98 +/- 21.11 fmol/mg protein and 53.39 +/- 7.01 fmol/mg protein respectively). The difference in AR between each two weeks was significant. Androgen promotes the development of tumor because of existence of AR, and its action may decline after establishment of tumor. Therefore, antiandrogen treatment may be ineffective after establishment of tumor.


Interstitial 6q21q23 duplication - variant of variable phenotype and incomplete penetrance or benign duplication?
Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known. We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members. Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.


Molybdenum disulfide nanoparticles concurrently stimulated biomass and β-carotene accumulation in Dunaliella salina.
Molybdenum disulfide nanoparticles (MoS2 NPs) hold tremendous properties in wide domain of applications. In this study, the impact of MoS2 NPs was investigated on algal physiological and metabolic properties and a two-stage strategy was acquired to enhance the commercial potential of Dunaliella salina. With 50 µg/L of MoS2 NPs exposure, cellular growth and biomass production were promoted by 1.47- and 1.33-fold than that in control, respectively. MoS2 NPs treated cells were subject to high light intensity for 7 days after 30 days of normal light cultivation, which showed that high light intensity gradually increased β-carotene content by 1.48-fold. Furthermore, analyses of primary metabolites showed that combinatorial approach significantly altered the biochemical composition of D. salina. Together, these findings demonstrated that MoS2 NPs at an optimum concentration combined with high light intensity could be a promising approach to concurrently enhance biomass and β-carotene production in microalgae.


[Clinical and angiographic observations in aneurysm of the membranous septum. Pathologenetic implications].
Aneurysm-like kialations of the membranous septum are described with increasing frequency in association to a ventricular septal defect (VSD). Their etiology may be congenital, though with different pathogenesis and acquired. An anatomical distinction between true aneurysm of the membranous septum and pseudoaneurysm is proposed. The acquired forms may be joined to a decrease of left to right shunt and are regarded as the mechanism of closure of a VSD. Nine cases of aneurysm-like dilation of the membranous septum are presented: an interpretation of their etiology and pathogenesis is discussed, on the basis of the history and clinical and instrumental data.


Effect of leg exercises on popliteal venous blood flow during prolonged immobility of seated subjects: implications for prevention of travel-related deep vein thrombosis.
Venous stasis is an important contributing factor in the development of travel-related deep vein thrombosis. This study examined factors affecting popliteal venous blood flow in order to determine the most effective exercise regimen to prevent venous stasis. Twenty-one healthy subjects were randomly assigned to various activities over a 9-week period. Subjects remained seated throughout the investigation and 3660 duplex ultrasound examinations were performed by a single examiner using a SonoSite 180 Plus handheld ultrasound. Baseline popliteal vein blood flow velocity, cross-sectional area and volume flow in subjects sitting motionless were assessed in the first 3 weeks.The remaining 6 weeks involved subjects performing airline-recommended activities, foot exercises, foot exercises against moderate resistance and foot exercises against increased resistance in order to determine the most beneficial method for enhancing popliteal venous flow. Sitting with feet not touching the floor and the effect of sleeping were also assessed. The median age of the subjects was 22 years (range: 18-25.5 years), height 171 cm (162.5-180.5 cm) and body mass index 25.3 kg m(-2) (23.2-26.3 kg m(-2)). Blood volume flow in the popliteal vein was reduced by almost 40% with immobility of seated subjects and by almost 2-fold when sitting motionless with feet not touching the floor. Foot exercises against increased resistance positively enhanced volume flow (P < 0.0001). Leg exercise regimens enhanced popliteal venous flow during prolonged immobility of seated subjects, reinforcing the importance of regular leg movement to prevent venous stasis during prolonged sitting, such as in long-distance travel.


Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer.
To determine the prophylactic properties of amifostine against acute and late toxicities from radiochemotherapy in patients with head-and-neck cancer. Fifty patients were randomized to receive conventional radiotherapy (RT) (2-Gy fractions, 5 days weekly, to a total of 60-74 Gy, depending on the tumor localization and TNM classification) and carboplatin (90 mg/m(2) infusion once per week before RT). Amifostine (300 mg/m(2)) was administered in the study group only 15-30 min before RT for 6-7.5 weeks. The primary study end point was the grading of acute and late nonhematologic toxicities (mucositis, dysphagia, xerostomia) induced by radiochemotherapy. Secondary end points included treatment duration, hematologic toxicity, and clinical outcome. The treatment duration was significantly shorter in the amifostine-treated group (p = 0.013), because treatment interruptions were more frequent in the control group. Acute toxicities (mucositis and dysphagia) were less severe in the amifostine-treated group. By Week 3, all in the control group experienced Grade 2 mucositis compared with only 9% in the amifostine-treated group (p <0.0001). By Week 5, 52.2% of the patients in the control group experienced Grade 4 mucositis compared with 4.5% in the amifostine-treated group (p = 0.0006). Similar results were obtained for dysphagia. At 3 months of follow-up, only 27% of patients in the study group experienced Grade 2 xerostomia compared with 73.9% in the control group (p = 0.0001). Eighteen months after cessation of therapy, the proportion of patients with Grade 2 xerostomia was 4.5% vs. 30.4% for each respective treatment group (p = 0.047). Cytoprotection with amifostine did not affect treatment outcome, with 90.9% complete responses in the amifostine-treated group compared with 78.3% in the control group (p = 0.414). Amifostine was effective in reducing mucositis and dysphagia resulting from radiochemotherapy in patients with head-and-neck cancer. Furthermore, amifostine reduced the severity of late xerostomia, a side effect of RT with long-lasting consequences. Amifostine treatment did not affect the clinical outcome.


Purtscher-like retinopathy following coronary artery bypass grafting in an antiphospholipid syndrome patient: a case report.
Purtscher retinopathy is a rare occlusive microangiopathy comprising a constellation of retinal signs including cotton wool spots, retinal hemorrhages and Purtscher flecken. While classical Purtscher must be antedated by a traumatic incident, Purtscher-like retinopathy is used to refer to the same clinical syndrome in the absence of trauma. Various non-traumatic conditions have been associated with Purtscher-like retinopathy e.g. acute pancreatitis, preeclampsia, parturition, renal failure and multiple connective tissue disorders. In this case study, we report the occurrence of Purtscher-like retinopathy following coronary artery bypass grafting in a female patient with primary antiphospholipid syndrome (APS). A 48-year-old Caucasian female patient presented with a complaint of acute painless diminution of vision in the left eye (OS) that occurred approximately two months earlier. Clinical history revealed that the patient underwent coronary artery bypass grafting (CABG) two months earlier and that visual symptoms started 4 days thereafter. Furthermore, the patient reported undergoing percutaneous coronary intervention (PCI) one year before for another myocardial ischemic event. Ophthalmological examination revealed multiple yellowish-white superficial retinal lesions i.e. cotton-wool spots, exclusively in the posterior pole and predominantly macular within the temporal vascular arcades only OS. Fundus examination of the right eye (OD) was normal and the anterior segment examination of both eyes (OU) was unremarkable. A diagnosis of Purtscher-like retinopathy was made based on clinical signs, suggestive history and consolidated by fundus fluorescein angiography (FFA), spectral domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA) of macula, optic nerve head (ONH) according to the diagnostic guidelines of Miguel. The patient was referred to a rheumatologist to identify the underlying systemic cause and was diagnosed with primary antiphospholipid syndrome (APS). We report a case of Purtscher-like retinopathy complicating primary antiphospholipid syndrome (APS) following coronary artery bypass grafting. This conveys a message to clinicians that patients presenting with Purtscher-like retinopathy should undergo meticulous systemic work-up in order to identify potentially life-threatening underlying systemic diseases.


Implementation of first episode psychosis intervention in India - A case study in a low-and middle-income country.
First Episode Psychosis (FEP) is a serious mental illness affecting adolescents and young persons. While many effective interventions are available, there has not been much research to understand the implementation of such interventions in India and other low- and middle-income countries (LMIC). We studied the implementation of an FEP intervention program in a specialist mental health facility in Chennai, India, using a well-established framework for doing so, the Consolidated Framework for Implementation Research (CFIR). We conducted 27 in-depth interviews with the service users (15 persons with FEP and 12 family caregivers of persons with FEP). We also conducted a focus group discussion with 8 service providers and in-depth interviews with 7 other service providers including those in the service management. A thematic analysis approach was used to identify emerging themes. First, we found CFIR effectively accommodated implementation challenges evident in LMICs; that is, it is transferable to LMIC settings. Second, we highlight barriers to implementation that include cost, limited human resources, cultural and professional hierarchy, divergence from evidence-based guidelines, and lack of awareness and stigma in the wider community. Third, we highlight facilitators for implementation such as, leadership engagement, the need for change that was recognized within the service, cosmopolitan perspectives derived from clinicians' local and international collaborative experiences and expertise, compatibility of the intervention with the existing systems within the organization, accommodating the needs of the service users, and rapport developed by the service with the service users. Fourth, we propose a model of service delivery incorporating a task-sharing approach for first episode psychosis in resource restricted settings based on the feedback from the stakeholders.


Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.
Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.


Characterization of pUL5, an HCMV protein interacting with the cellular protein IQGAP1.
Among the Herpesviridae, human cytomegalovirus (HCMV) owns the largest genome and displays a huge coding potential. Here, we characterized the UL5 gene product (pUL5) of the clinical isolate TR strain. The protein was predicted as a 166-amino-acid membrane protein with a theoretical mass of 19 kDa. Recombinant virus expressing pUL5 with a tag allowed the identification of two pUL5 non-glycosylated species of approximately 19 and 9 kDa, expressed with early and late kinetic respectively. Experiments in infection confirmed that the lower molecular weight species was translated from an internal ATG in the UL5 open reading frame. Confocal microscopy analysis showed that pUL5 localized within the assembly compartment, but is not incorporated in the virion, as shown by Western blot on purified viral particles. Finally, pull-down experiments coupled with mass spectrometry analysis identified IQGAP1 as a pUL5 interactor, giving new hints on possible roles of pUL5 during HCMV infection.


Selective expression of transthyretin in subtypes of lung cancer.
Transthyretin (TTR) is expressed primarily in liver, choroid plexus of brain and pancreatic islet A and B cells. It is also synthesized in some endocrine tumors. In the present study, the protein expression of TTR in lung cancer tissues and cell lines was investigated by western blot. The mRNA expression of TTR in 24 pairs of frozen lung cancer tissues was examined by RT-PCR. The specific expression and cellular distribution of TTR were also evaluated in 104 paraffin-embedded lung cancer samples and 3 normal lung tissues by immunohistochemistry. Similarly, the subcellular localization and expression of TTR were further analyzed in lung cancer cell lines. With the exception of mucinous adenocarcinoma, the expression of TTR protein was observed in all tested subtypes of lung carcinoma. Adenocarcinoma displayed the highest positive expression rate of TTR, accounting for 84.4 %, and the positive expression rate of TTR was up to 85.7 % at stages III and IV. The secretory bubbles with strong TTR staining were observed in luminal cells of lung cancer. Furthermore, the localization of TTR in the cytoplasm of lung cancer cells and the secretion of TTR into extracellular milieu were also confirmed. Taken together, TTR is selectively synthesized in lung cancer cells and can be secreted extracellularly.


Inhibition of spontaneous growth and induced differentiation of murine erythroleukaemia cells by paraquat and atrazine.
The effect of the herbicides paraquat and atrazine on erythroid differentiation has been studied in mouse erythroleukaemic cells. The addition of atrazine or paraquat was shown to inhibit both spontaneous growth and hexamethylene-bis-acetamide (HMBA)-induced differentiation of undifferentiated erythroleukaemic cells. This effects was dose-dependent and occurred at concentrations of less than 10 ppm for both herbicides. Growth inhibition with atrazine (40-45%) was less pronounced than with paraquat (85-90%). Inhibition of differentiation paralleled growth inhibition. A synergistic effect was observed with HMBA, which per se reduced the growth rate of mouse erythroleukaemic cells, and either herbicide. Evaluation of cell viability under all the experimental conditions using either a trypan blue dye exclusion test or labelled chromium indicated that the effects observed were not related to a cytocidal action of atrazine or paraquat.


Modified halloysite nanotubes reduce the toxic effects of zearalenone in gestating sows on growth and muscle development of their offsprings.
Zearalenone (ZEN) is an estrogenic mycotoxin that is primarily produced by Fusarium fungi and has been proven to affect the reproductive capacity of many species to varying degrees. The present experiment was designed to study the maternal persistent effects of zearalenone toxicity in gestating sows on growth and muscle development of their offsprings, and the alleviation of zearalenone toxicity by modified halloysite nanotubes (MHNTs). Eighteen sows were fed with one of three dietary treatments that included the following: (1) a control diet, (2) a contaminated grain diet (with 50 % moldy corn, 2.77 mg/kg ZEN), and (3) a contaminated grain diet (with 50 % moldy corn, 2.76 mg/kg ZEN) + 1 % MHNTs. Each sow was exclusively fed its experimental diets from 35 to 70 d of gestation at a total of 2 kg daily. Muscle samples were collected from six piglets per treatment at birth, weaning and finishing. The results showed that feeding the sows with the ZEN-contaminated diets from 35 to 70 d of gestation decreased the ADG, ADFI and G:F of their offsprings (P < 0.05). The muscle fiber numbers in the newborn, weaning and growing-finishing pigs and the muscle fiber diameters at birth and weaning were also decreased by maternal ZEN exposure (P < 0.05). The expressions of IGF-I, IGF-II, Myf-5 and Mstn at birth and IGF-II, Pax7, Myf-5 and MyoD1 at weaning were altered by feeding gestating sows with ZEN-contaminated diets (P < 0.05). The MHNTs reduced most of the ZEN-induced toxic effects: the ADG and ADFI on growth performance, the muscle fiber numbers at weaning and finishing and the muscle fiber diameters at weaning (P < 0.05). The expression levels of IGF-II and Mstn in newborn piglets and IGF-II and Myf-5 in weaning piglets were also prevented by adding 1 % MHNTs (P < 0.05). The present study demonstrated that the offsprings of sows fed with ZEN-contaminated diets from 35 to 70 day of gestation exhibited weakening on growth performance, physiological changes in their muscle fibers and alterations of mRNA expression in their muscle tissues, and also indicated that MHNTs prevented most of the ZEN-induced weakening in the muscle tissues.


Necrotizing lymphadenitis: Not always tuberculosis, its Kikuchi-Fujimoto's disease.
Kikuchi-Fujimoto's disease is an uncommon self limiting, benign cause of generalised lymphadenopathy with fever. It can present as a triad of fever, night sweats and lymphadenopathy which resembles more common causes like tuberculosis and lymphoma. Being an endemic country a patient may be treated on the lines of tuberculosis often. We present case of a young female who was diagnosed as Kikuchi-Fujimoto's disease after not responding to antitubercular treatment. Pathologists and Clinicians must be aware of this condition to prevent unnecessary treatment.


Sustained "slow-fast" and "fast-slow" AV nodal re-entrant tachycardia in a patient with recurrent supraventricular tachycardia.
A case is presented of a 21-year-old woman with recurrent paroxysmal supraventricular tachycardia. Electrophysiologic study demonstrated the presence of both antegrade and retrograde dual AV nodal conduction pathways and both conventional slow-fast and atypical fast-slow forms of the AV nodal re-entrant tachycardia could be induced. Both tachycardias were successfully suppressed with a combination of digoxin and verapamil.


Cervicofacial non-tuberculous mycobacteria: A report of 30 cases.
Mycobacterial infection is the most common cause of cervical granuloma, implicating either a tuberculous or a non-tuberculous mycobacterium (NTM). NTM is a ubiquitous organism, found in soil, water, food, etc. The most frequently implicated is Mycobacterium avium-intracellular. Most authors agree that NTM is increasingly isolated, due to a decrease in vaccination rates. Initial diagnosis is difficult and management is not clearly codified. A retrospective study conducted in the University Hospital of Nantes, France, between 2005 and 2014, included all patients treated for head and neck NTM lymphadenitis. The research was conducted on the database of the institution's bacteriology department. Population, history, symptoms and diagnostic features were noted. Treatment, surgical complications, adverse reactions to antibiotics, patient adherence, antibiotic therapy duration, time to remission and prognosis were analyzed. Between 2005 and 2014, 30 patients were diagnosed with head and neck NTM lymphadenitis: 17 female, 13 male; mean age at diagnosis, 4.5 years. Locations were submandibular (n=16), parotid, (n=7), cervical (n=5), parapharyngeal (n=4) and, for 1 patient, in the auricle concha. Eight patients received first-line surgical treatment, which was effective in 75% of cases, 2 patients requiring additional antibiotic therapy. Twenty-two patients were treated with first-line antibiotherapy, which was effective in 90% of cases. There were no relapses at a mean 32 weeks' follow-up. Total resection of all affected nodes and infiltrated subcutaneous fatty tissue is the treatment of choice. Drug therapy (including at least a macrolide) seems indicated only in case of incomplete resection or if surgery would entail functional and/or esthetic risk. Increased incidence, since BCG vaccination was stopped, will continue to confront the practitioner with an infantile disease in which management must be multidisciplinary.


Localization of renal kallikrein in the dog.
Renal kallikrein was estimated in glomerular, tubular and medullary fractions of dog kidneys. It was found primarily in the cortex, the highest level of activity being detected in glomeruli-rich fraction. These results support previous observation that kallikrein may be associated with the juxta-glomerular complex.


Responses to Ixekizumab in Male and Female Patients with Psoriatic Arthritis: Results from Two Randomized, Phase 3 Clinical Trials.
Differences in psoriatic arthritis (PsA) treatment response between sexes for ixekizumab, an interleukin-17A antagonist, are largely unexplored. This analysis used data from randomized clinical trials (RCTs) evaluating ixekizumab to study differences in treatment response between male and female patients with PsA. We used pooled data from patients enrolled in SPIRIT-P1 and SPIRIT-P2 (NCT01695239 and NCT02349295, respectively), phase 3 RCTs evaluating ixekizumab every 4 and 2 weeks in patients with active PsA. Subgroups of patients were defined by sex (male, female). Efficacy was measured by the proportion of male and female patients achieving American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70), minimal disease activity or very low disease activity (MDA/VLDA), and Disease Activity Index for Psoriatic Arthritis (DAPSA) scores representing low disease activity (LDA) or remission through week 156. Changes from baseline in components of the above measures were also assessed through week 156. Compared to male patients at baseline, female patients were older, had higher body mass index and lower C-reactive protein levels, and had worse tender joint count, Health Assessment Questionnaire Disability Index, and Leeds Enthesitis Index scores. Through week 156, female patients in all treatment arms had lower response rates than male patients in all analyzed composite measures (ACR20/50/70; MDA/VLDA; DAPSA LDA/remission), with significant differences observed at multiple timepoints in both ixekizumab treatment arms. Female patients also had smaller numeric changes from baseline in the composite measures' individual components. Compared to female patients, male patients had greater response rates in ACR20/50/70, MDA/VLDA, and DAPSA LDA/remission and numerically larger improvements in these measures' individual components, although clinical significance is unclear. Continued efforts to understand sex differences in treatment response may provide insights that can help optimize clinical decision making. ClinicalTrials.gov identifiers, NCT01695239 and NCT02349295.


Five-Year Outcomes of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Class I Obesity.
Bariatric surgery is being recognized increasingly as an effective treatment for obesity and related comorbidities. In Japan, the cost of laparoscopic sleeve gastrectomy (LSG) is covered by the national health insurance for adults with a body mass index (BMI) ≥ 35 kg/m2 and specific comorbidities (type 2 diabetes mellitus (T2DM), hypertension (HT), dyslipidemia (DL), and obstructive sleep apnea syndrome (OSAS)). However, only 0.6% of the adult population have a BMI ≥ 35 kg/m2. In contrast, 4.3% have class I obesity (a BMI of 30-34.9 kg/m2). The BMI of Asians with central obesity-induced diabetes and other metabolic disorders is much lower than that of Westerners. To evaluate the medium-term (up to 5 years) outcomes of LSG performed in Japanese patients with class I obesity. One hundred eighteen consecutive patients with class I obesity treated by LSG at our center between August 2007 and December 2018 were included in a retrospective study. Mean preoperative body weight (BW) and BMI were 88.6 ± 10.3 kg and 32.8 ± 1.6 kg/m2, respectively. Weight loss, comorbidity status, and adverse events were assessed. Mean BW/BMI at 1, 3, and 5 years after LSG decreased significantly to 66.6 ± 11.2 kg/24.6 ± 2.8 kg/m2, 68.0 ± 14.0 kg/25.4 ± 4.0 kg/m2, and 69.1 ± 12.9 kg/26.5 ± 3.0 kg/m2, respectively. Mean total weight loss at 1, 3, and 5 years was 24.7 ± 8.2%, 21.8 ± 12.1%, and 18.5 ± 9.7%, respectively. Metabolic disorders such as T2DM, HT, and DL improved significantly. There was no mortality. LSG is safe, yields excellent weight loss, and improves obesity-related comorbidities in Japanese patients with class I obesity.


Splenectomy for treatment of gastric cancer: Japanese experience.
Surgery for gastric cancer in Japan has frequently been combined with resection of the spleen (splenectomy) or of the pancreatic body and tail and spleen (pancreatosplenectomy, PS). Splenectomy in patients with gastric cancer has been performed with two major purposes in mind: (1) curability of the cancer and (2) immunologic reasons. Direct cancerous invasion to the pancreas requires PS, although examination of these cases revealed that in 34.3% of such macroscopic invasions only fibrous adhesion to pancreas existed. Metastases to lymph nodes at the splenic hilus (no. 10) or along the splenic artery (no. 11) also required splenectomy. The incidences of no. 10 or no. 11 lymph node metastasis were as high as 26.7% and 22.2% respectively, for cancers of whole stomach, and 15.5% and 12.1% for cancers of the upper portion of stomach. Concerning the immunologic aspect of splenectomy for gastric cancer, the reports of fundamental research and clinical studies suggest that the spleen plays sometimes acts as a suppressor and at other times as a helper to the tumor activity, according to the number of tumor cells. From these data, we concluded that the spleen should be preserved in stage I, II, and III patients with curative operation; for stage IV patients the spleen should be resected. The immunologic significance of splenectomy should be clarified precisely in the near future.


Biological activities of thionated thyrotropin-releasing hormone analogs.
Analogs of thyrotropin-releasing hormone (Glp-His-Pro-NH2, TRH) have been prepared which contain thioamide moieties in the pyroglutamic acid ring, the carboxyamide proline terminus, and in both positions (dithio). These compounds have been tested for TSH-releasing activities (in vitro and in vivo), and for binding to TRH receptors in rat pituitary and cortex. The monothionated analogs showed no significant differences in TSH-releasing potency from TRH either in vitro or in vivo. However, with two thioamide replacements the potency decreases about 50%. Significantly, in terms of receptor selectivity, thionation has resulted in differentiation between brain receptors (pituitary and cortex). The Pro psi[CSNH2] and dithio analogs were more selective (higher affinity to pituitary receptors) than the parent hormone, while the analog containing a thioamide replacement in the pyroglutamyl ring had lower affinity and was not selective. These results suggest that the subtle exchange of sulphur for oxygen can have an important impact on both receptor selectivity and affinity within a biologically active peptide.


Design and functional expression in Escherichia coli of a synthetic gene encoding Clostridium pasteurianum 2[4Fe-4S] ferredoxin.
A gene encoding the exact sequence of Clostridium pasteurianum 2[4Fe-4S] ferredoxin and containing 11 unique restriction endonuclease cleavage sites has been synthesized and cloned in Escherichia coli. The synthetic gene is efficiently expressed in E. coli and its product has been purified and characterized. The N-terminal sequence is identical to that of the protein isolated from C. pasteurianum and the recombinant ferredoxin contains the exact amount of [4Fe-4S] clusters (2 per monomer) expected for homogeneous holoferredoxin. It displays reduction potential and kinetic parameters as electron donor to C. pasteurianum hydrogenase I identical to those determined for the native ferredoxin. All of these properties demonstrate that the 2[4Fe-4S] ferredoxin expressed in E. coli is identical to the parent clostridial protein.


Idiopathic pulmonary fibrosis: Disease mechanisms and drug development.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.