Trimethylsilyl Chloride-Modified Li Anode for Enhanced Performance of Li-S Cells.
A facile and effective method to modify Li anode for Li-S cells by exposing Li foils to tetrahydrofuran (THF) solvent, oxygen atmosphere and trimethylsilyl chloride ((CH3)3SiCl) liquid in sequence is proposed. The results of SEM and XPS show the formation of a homogeneous and dense film with a thickness of 84 nm on Li metal surface. AC impedance and polarization test results show the improved interfacial stability. The interfacial resistances as well as polarization potential difference have obviously decreased as compared with that of a pristine Li anode. CV and charge-discharge test results demonstrate that more reversible discharge capacity and higher Coulombic efficiency can be achieved. Specific capacity of 760 mAh g(-1) and an average Coulombic efficiency of 98% are retained after 100 cycles at 0.5C without LiNO3 additive. Additionally, the Li-S cell with a modified Li anode displays a greatly improved rate performance with ∼425 mAh g(-1) at 5C, making it more attractive and competitive in the applications of high-power supply.


Antibody and delayed-type hypersensitivity responses to Ochrobactrum anthropi cytosolic and outer membrane antigens in infections by smooth and rough Brucella spp.
Immunological cross-reactions between Brucella spp. and Ochrobactrum anthropi were investigated in animals and humans naturally infected by Brucella spp. and in experimentally infected rams (Brucella ovis infected), rabbits (Brucella melitensis infected), and mice (B. melitensis and Brucella abortus infected). In the animals tested, O. anthropi cytosolic proteins evoked a delayed-type hypersensitivity reaction of a frequency and intensity similar to that observed with B. melitensis brucellin. O. anthropi cytosolic proteins also reacted in gel precipitation tests with antibodies in sera from Brucella natural hosts with a frequency similar to that observed with B. melitensis proteins, and absorption experiments and immunoblotting showed antibodies to both Brucella-specific proteins and proteins common to Brucella and O. anthropi. No antibodies to O. anthropi cytosolic proteins were detected in the sera of Brucella-free hosts. Immunoblotting with sera of Brucella-infected sheep and goats showed immunoglobulin G (IgG) to Brucella group 3 outer membrane proteins and to O. anthropi proteins of similar molecular weight. No IgG to the O-specific polysaccharide of O. anthropi lipopolysaccharide was detected in the sera of Brucella-infected hosts. The sera of sheep, goats, and rabbits infected with B. melitensis contained IgG to O. anthropi rough lipopolysaccharide and lipid A, and B. ovis and O. anthropi rough lipopolysaccharides showed equal reactivities with IgG in the sera of B. ovis-infected rams. The findings show that the immunoresponse of Brucella-infected hosts to protein antigens is not necessarily specific for brucellae and suggest that the presence of O. anthropi or some related bacteria explains the previously described reactivities to Brucella rough lipopolysaccharide and outer membrane proteins in healthy animals.


Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways.
Non-rapid eye movement (NREM) sleep, characterized by slow-wave electrophysiological activity, underlies several critical functions, including learning and memory. However, NREM sleep is heterogeneous, varying in duration, depth, and spatially across the cortex. While these NREM sleep features are thought to be largely independently regulated, there is also evidence that they are mechanistically coupled. To investigate how cortical NREM sleep features are controlled, we examined the astrocytic network, comprising a cortex-wide syncytium that influences population-level neuronal activity. We quantified endogenous astrocyte activity in mice over natural sleep and wake, then manipulated specific astrocytic G-protein-coupled receptor (GPCR) signaling pathways in vivo. We find that astrocytic Gi- and Gq-coupled GPCR signaling separately control NREM sleep depth and duration, respectively, and that astrocytic signaling causes differential changes in local and remote cortex. These data support a model in which the cortical astrocyte network serves as a hub for regulating distinct NREM sleep features.


A simple pressure-assisted method for MicroED specimen preparation.
Micro-crystal electron diffraction (MicroED) has shown great potential for structure determination of macromolecular crystals too small for X-ray diffraction. However, specimen preparation remains a major bottleneck. Here, we report a simple method for preparing MicroED specimens, named Preassis, in which excess liquid is removed through an EM grid with the assistance of pressure. We show the ice thicknesses can be controlled by tuning the pressure in combination with EM grids with appropriate carbon hole sizes. Importantly, Preassis can handle a wide range of protein crystals grown in various buffer conditions including those with high viscosity, as well as samples with low crystal concentrations. Preassis is a simple and universal method for MicroED specimen preparation, and will significantly broaden the applications of MicroED.


MicroRNA-125b: association with disease activity and the treatment response of patients with early rheumatoid arthritis.
MicroRNAs (miRNAs) are small RNAs that regulate gene expression by targeting mRNA. It was proved that some miRNAs are significantly deregulated in rheumatoid arthritis (RA). MicroRNA-125b negatively regulates expression of TNF-α, which plays a crucial role in RA pathogenesis. The aim of this study was to determine the treatment outcome of patients with early RA based on the expression of circulating and cellular miR-125b. Total RNA was isolated from the plasma and peripheral blood mononuclear cells (PBMCs) of 58 patients with early RA before and three months after treatment initiation and of 54 age- and sex-matched healthy controls (HC). The expression of miR-125b was measured by TaqMan quantitative PCR. The treatment responders were defined as patients achieving remission or low disease activity (28-joint count disease activity score (DAS28) <3.2). Receiver operating characteristic (ROC) curve and stepwise backward multivariable logistic regression analyses of miR-125b expression were used to predict the disease outcome at three and six months after initiation of treatment. The expression of miR-125b in the PBMCs and plasma of treatment-naïve early RA patients was significantly lower than that of HC and increased significantly after three months of treatment, particularly in responders. However, only the cellular expression of miR-125b was inversely correlated with disease activity. MiR-125b expression in PBMCs was higher in responders than in non-responders after three months (p = 0.042). Using ROC analysis, the cellular expression of miR-125b, but not the disease activity at baseline, predicted the treatment response after three months of therapy (area under the curve 0.652 (95 % CI 0.510 to 0.793); p = 0.048). The expression of miR-125b in PBMCs of treatment-naïve patients may present a novel biomarker for monitoring the treatment outcome during the early phase of RA.


Non-invasive measurement of long bone cross-sectional moment of inertia by photon absorptiometry.
The use of the Norland-Cameron Bone Mineral Analyzer (BMA) to measure the cross-sectional moment of inertia of the mineral in a long bone is described and data regarding the usefulness and precision of the method are presented. The correlation coefficients between BMA-measured CSMI and that obtained from cross-sectional geometry were 0.99 both for a series of aluminum tubes and five bones of different sizes. The BMA-measured CSMI was linearly correlated with the CSMI digitized from cross-sections of a series of human ulnas at the r = 0.92 and 0.95 level in the AP and ML directions, respectively. The BMA-measured CSMI also correlated well with the torsional and bending behavior of ulnar specimens. Finally, a method for estimation the CSMI of a long bone section from BMA readings of mineral content and bone width is described. A linear correlation of r = 0.98 with the CSMI digitized from sections of human radii is demonstrated.


Amnioreduction vs expectant management in pregnancies with moderate to severe polyhydramnios.
The rate of polyhydramnios is higher in pregnancies complicated by congenital anomalies. These pregnancies have higher rates of peripartum complications. Amnioreduction is offered to relieve maternal symptoms such as dyspnea, abdominal and respiratory discomfort, and other issues like satiety. This study aimed to report the rates of amnioreduction and its associated complications in pregnancies with moderate to severe polyhydramnios secondary to fetal anomalies. We also sought to determine if amnioreduction provided additional benefits, including prolongation of pregnancy and a decrease in the rates of peripartum morbidities associated with moderate to severe polyhydramnios. This was a retrospective review of anomalous singleton pregnancies with moderate to severe polyhydramnios that were evaluated and delivered at a single center between 2013 and 2021. Peripartum outcomes were compared between pregnancies that underwent amnioreduction and those that were expectantly managed. Mann-Whitney U tests were used to compare continuous variables and Fisher's exact tests were used for categorical variables. A multiple regression model was created to understand the effects of amnioreduction on gestational age at delivery. A total of 218 singleton pregnancies met the inclusion criteria of moderate to severe polyhydramnios in the study period. Of those, 110 patients (50.5%) underwent amnioreduction and 108 patients (49.5%) opted for expectant management. A total of 147 procedures were performed at a median gestational age of 32.5 weeks and a median of 1900 mL of amniotic fluid was removed per procedure. Complications occurred in 10.9% (n=16) of procedures, including preterm delivery within 48 hours in 5.4% cases (n=8). The median amniotic fluid index was higher in the amnioreduction group than in the expectant group (38.9 cm vs 35.5 cm; P<.0001). Patients who underwent amnioreduction had an earlier median gestational age at delivery (36.3 weeks vs 37.0 weeks; P=.048), however, the rates of spontaneous preterm delivery were similar. A higher percentage of women in the amnioreduction group had vaginal delivery (49.4% vs 30.5%; P=.01) and lower rates of uterine atony (2.4% vs 13.7%; P=.006). In the multiple linear regression analysis, the gestational age at delivery positively correlated with gestational age at amnioreduction after controlling for amniotic fluid volume (P<.0001; 95% confidence interval, 0.34-0.71). In addition, the patients in the amnioreduction group were twice as likely to have a vaginal delivery (P=.02). Amnioreduction in the setting of moderate-severe polyhydramnios has a reasonably low rate of complications but does not provide any benefits in terms of prolonging the pregnancy. The procedure may increase the likelihood of vaginal delivery and lower the rates of uterine atony.


Clinical epidemiological analysis of the mortality rate of liver transplant candidates living in rural areas.
MELD score has been used to predict 90-day mortality of subjects listed for liver transplantation (OLT). Validation of MELD score for patients on the waiting list in transplant programmes serving rural areas in North America is lacking. A retrospective cohort of patients affected by end-stage liver disease was studied to assess the mortality rate within 90 days after being listed at our transplant centre. Secondary aims were to identify differences between predicted and observed 90-days mortality using MELD and MELDNa scores at the time of listing. Among 126 patients included in this study, waiting list mortality was 35.0%. Ninety-day mortality was 21.1%, which was significantly greater than the mortality estimated by the MELD (9.1%, 95% CI: 6.6-11.5) and MELDNa (9.3%, 95%CI: 6.0-12.5). Despite this underestimation, AUC for MELD and MELDNa was 0.80 and 0.78 respectively. In our study, independent predictors of waiting list mortality were age, diagnosis of cholestatic disease and residence over 500 km from our transplant centre. MELD and MELDNa underestimated the 90-day mortality in patients with liver failure living in rural areas. Validation of these models should be performed in other transplant centres serving patients with limited access to specialized services.


Dermatologic lesions in a transplant population.
Many authors have reported an increase in the incidence of skin neoplasia in renal transplant patients. Two hundred and twenty-three patients, who received a renal transplants between 1965 and 1984, were examined for the presence of skin lesions. There was a high incidence of simple warts (24%) and hyperkeratoses (21%). Frank malignancy had developed in 9 patients; this is more than 4 times the expected incidence for the population of Northern Ireland.


Fast-track rehabilitation following video-assisted pulmonary sublobar wedge resection: A prospective randomized study.
Postoperative morbidity and inhospital length of stay are considered major determinants of total health care expenditure associated with thoracic operations. The aim of this study was to prospectively evaluate the role of video-assisted thoracic surgery (VATS) compared to mini-muscle-sparing thoracotomy in facilitating early recovery and hospital discharge after pulmonary sublobar wedge resections. A total number of 120 patients undergoing elective pulmonary sublobar wedge resection were randomly assigned to VATS (n = 60) or mini-muscle-sparing thoracotomy (n = 60). The primary endpoint was time to hospital discharge. Postoperative complications, cardiopulmonary morbidity and 30-day mortality served as secondary endpoints. Patients' baseline demographic and clinical data did not differ among study arms as well as the number of pulmonary segments resected and the morphology of the nodular lesions. Total hospital stay was significantly shorter in patients assigned to the thoracoscopic technique as opposed to those who were operated using the mini-muscle-sparing thoracotomy approach (4 ± 0.6 versus 4.4 ± 0.6 days respectively, P = 0.006). Multivariate analysis revealed that VATS approach was inversely associated with longer inhospital stay whereas the number of resected segments was positively associated with an increased duration of hospitalization. Patients in the VATS group were less likely to develop atelectasis (≥1 lobe) compared to those who underwent thoracotomy (0% versus 6.7% respectively, P = 0.042). Kaplan-Meier analysis revealed similar 30-day mortality rates in both study arms (Log-rank P = 0.560). VATS was associated with shorter duration of hospitalization positively affecting the patients' quality of life and satisfaction. Significant suppression of the total cost of recovery after thoracoscopic pulmonary resections is expected.


Mesenchymal Stem Cell (MSC) Aggregate Formation in vivo.
Human mesenchymal stem/progenitor cells (MSCs) isolated from various adult tissues show remarkable therapeutic potential and are being employed in clinical trials for the treatment of numerous diseases (Prockop et al., 2010). While routes of cell administration vary, profound beneficial effects of MSCs in animal models have been observed following intraperitoneal injections of the cells (Roddy et al., 2011). Similar to MSC spheres formed in culture under conditions where attachment to plastic is not permitted (Bartosh et al., 2010), MSCs injected into the peritoneum of mice spontaneously aggregate into 3D sphere-like structures (Bartosh et al., 2013). During the process of sphere assembly and compaction, MSCs upregulate expression of numerous therapeutic anti-inflammatory and immune modulatory factors. Here we describe the method we previously used for the generation of human bone marrow-derived MSC aggregates/spheres in vivo (Bartosh et al., 2013). By tagging the MSCs with green fluorescent protein (GFP), the aggregates formed can be easily visualized, collected and analyzed for changes in cellular properties and interactions with host immune cells.


Neutralizing and complement-dependent enhancing antibodies in different stages of HIV infection.
Reclustering and indirect immunofluorescence assays on MT-4 cells [carrying both CD4 and complement receptor type 2 (CR2)] were used to measure neutralizing and enhancing antibodies in sera obtained from HIV-1-infected individuals. Heat-inactivated sera were tested before and after mixing 1:1 with fresh seronegative human serum. Using heated samples, neutralizing antibodies were found in 20 out of 20 and 11 out of 19 serum samples of asymptomatic and symptomatic [AIDS, AIDS-related complex (ARC)] HIV-seropositive patients, respectively. In complement-restored samples, neutralizing activity was found in eight sera of asymptomatic patients and in none of the sera of AIDS and ARC patients; enhancing activity could be detected in four and 12 sera, respectively. A significant positive correlation was observed between the titres of neutralizing antibodies measured in the complement-restored samples and the absolute number of CD4+ lymphocytes. These findings indicate that the appearance of complement-dependent enhancing antibodies coincident with the loss of neutralizing antibodies may indicate a poor prognosis in HIV infection.


Effect of cyclodextrins on the hydrolysis of an oxazolidine prodrug of (1R,2S)-(-)-ephedrine-cis-2-(4-methoxyphenyl)-3, 4-dimethyl-5-phenyloxazolidine.
Molecular complexes of an oxazolidine prodrug of (-)-ephedrine, cis-2-(4-methoxyphenyl)-3,4-dimethyl-5-phenyloxazolidine, with alpha-, beta-, dimethyl-beta- (DM-beta-) and hydroxypropl-beta- (HP-beta-) cyclodextrins (CDs) were examined using ionspray mass spectrometry. The results suggest, under our experimental conditions, a 1:1 stoichiometric complex between the prodrug and all CDs. Apart from the putative inclusion complexation, the stabilization effect of CDs on the prodrug in an aqueous solution was studied. beta-, DM-beta- and HP-beta-CD exhibited a retardation effect on the rate of hydrolysis of the prodrug. Conversely, alpha-CD did not alter the rate of hydrolysis even at excess concentrations. Presumably, the larger cavity diameter of beta-CDs may permit a greater depth of penetration of the prodrug, resulting in its shielding from hydrolysis. The observations in this work indicate that mass spectrometry could be a rapid and informative analytical method to aid in the preliminary evaluation of the potential utility of CDs in enhancement of drug stability.


Current status of intraoperative real-time vibrography in neurosurgery.
Intracranial lesions are often characterized by different elasticities. The aim of the present study was to test the application of vibrography during brain tumor surgery. The real-time vibrography system consisted of a conventional ultrasound system (Siemens Sonoline Omnia) with a custom-designed RF interface and a 6.5-MHz endocavity curved array (Siemens 6.5EC10). The RF data were digitized using a 50-MHz, 12-bit PCI analog/digital (A/D) converter for real-time or offline processing. Static compression was replaced by low-frequency axial vibration of the probe. A special applicator equipped with a stepping motor moved the ultrasonic probe and produced a low frequency mechanical vibration of 5-10 Hz with a vibration amplitude of 0.3 mm and slight preliminary compression (total<1 mm). The maximum application time was 60 sec. A pneumatic holding device (Unitrac, Aesculap, Tuttlingen, Germany) was used. Brain tissue is normally color coded between red and orange. In this study 41 out of 45 tumors could be detected via vibrography. Two tumors could not be detected with this imaging technique: a glioblastoma at a depth of 2 cm and a metastasis at a depth of 3 cm. Two additional tumors were not recognized because of technical problems. In 4 cases tumors with strain values identical to those in brain tissue (coded red or orange) but easily identified by a peripheral zone of high strain (yellow) were found. Tumors with strain values higher than those measured in brain tissue coded yellow and were softer than brain during surgical intervention. Higher strain was found in 23 tumors. Tumors with strain values lower than those in cerebral tissue were found to be harder during surgery and coded brown or black. Lower strain was found in 10 cases. Four tumors were inhomogeneous and could not be assigned to one of the above groups. Mortality was 0%, morbidity 2.3%. One patient displayed transient paresis of the lower extremity due to microsurgical difficulties during the approach. In one patient minimal bleeding of the cortical surface occurred in a frontobasal tumor; however, no postoperative deficits were noted. Vibrography is a new low-risk technique for intraoperative imaging. In low-grade astrocytomas and oligodendrogliomas, this additional technique can be used to control resection. In other cortical and subcortical tumors (e. g. metastases), it can provide an impression of the intratumoral elasticities.


[Protective effect of urinastatin on ischemic renal injury in rabbits].
Protective effect of urinastatin on ischemic renal injury in rabbits was investigated by urinary enzymes and renal function tests. Ten rabbits were divided into two groups: the control group and urinastatin group administered 50,000 units/kg of urinastatin. The ischemic renal injury model was made by occluding the left renal artery for 60 minutes. Urinary excretions of N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GTP) (U-NAG and U-gamma-GTP), creatinine clearance (Ccr), free water clearance (CH2O), fractional excretion of sodium (FENa) and urine volume (UV) were measured before occlusion of the left renal artery and after reflow. There were no significant differences in the values before occlusion (baseline values) for U-NAG, U-gamma-GTP, Ccr, CH2O, FENa, and UV between the two groups. U-NAG after reflow was increased in the two groups compared with baseline values, and the increase was significantly lower in the urinastatin group than control group. U-gamma-GTP after reflow was also increased in the two groups compared with baseline values, but the change was not significant between the two groups. Ccr and CH2O after reflow were significantly decreased, and FENa and UV were increased in the two groups compared with baseline values. However, no significant differences were observed between the two groups in these four parameters. These results suggest that urinastatin is effective for the protection of the kidney against ischemic damage, especially of the renal tubular cells.


Advances in recognition and treatment of social anxiety disorder: a 10-year retrospective.
Social anxiety disorder frequently begins in early life and is associated with the subsequent development of comorbid conditions such as depressive and substance use disorders. Social anxiety disorder, particularly the generalized subtype, is characterized by marked impairment in numerous functional domains, including education and social relations. Paroxetine, the first medication to receive an indication in the United States for the treatment of social anxiety disorder, has been shown to be effective in 50% to 60% of patients. The mechanism of action of paroxetine in the treatment of social anxiety disorder is at present unclear. A possible role for early treatment to prevent complications of social anxiety disorder should be explored.


Surgical Treatment of a Patient with a Solitary Thyroid Metastasis from Primary Sigmoid Adenocarcinoma: A Case Report and Literature Review.
Malignant metastases to the thyroid are rare and even rarer from colorectal cancer (CRC). Most cases of CRC metastasis to the thyroid involve metastases to other organs as well, particularly the liver and/or lung. There are only three reports of CRC metastasizing to the thyroid without involvement of another site. Patients with solitary thyroid metastasis from CRC have a poor prognosis after surgery, whereas resection is beneficial in their counterparts with a solitary liver or lung metastasis. This difference could be the result of delayed diagnosis of thyroid metastasis in patients with CRC, given that postoperative follow-up examination of the thyroid is not routinely performed. Here we describe a patient who was found to have a solitary metastasis of sigmoid cancer to the thyroid on postoperative imaging and has had prolonged disease-free survival after thyroidectomy. Our experience suggests that a low threshold of suspicion is crucial for timely diagnosis of thyroid metastasis from CRC and that resection can improve disease-free survival.


[Controversy and progress on whether to retain left colonic artery in radical resection of rectal cancer].
Japanese Society for Cancer of the Colon and Rectum (JSCCR) guideline 2019 recommended that lymph node dissection for advanced rectal cancer should include the lymphatic adipose tissue at the root of the inferior mesenteric vessels, but the ligation site of the inferior mesenteric artery (IMA) was not determined, and the NCCN guideline did not indicate clearly whether to retain the left colonic artery (LCA). Controversy over whether to retain LCA is no more than whether it can reduce the incidence of anastomotic complications or postoperative functional damage without affecting the patients' oncological outcome. Focusing on the above problems, this paper reviews the latest research progress. In conclusion, it is believed that the advantages of retaining LCA are supported by most studies, which can improve the blood supply of the proximal anastomosis, and technically can achieve the same range of lymph node dissection as IMA high ligation. However, whether it affects the survival of patients, reduces the incidence of anastomotic leakage, and improves the quality of life of patients, more high-quality evidence-based medical evidence is still needed.


[Clinicopathological features of hepatic fibrinogen storage disease in children].
Objective: To investigate the clinicopathological and molecular characteristics of hepatic fibrinogen storage disease (FSD) in children. Methods: The clinical, histopathologic, immunophenotypic, ultrastructural and gene sequencing data of 4 FSD cases were collected from September 2019 to January 2021 in the Children's Hospital of Fudan University, Shanghai, China. Retrospective analysis and literature review were conducted. Results: There were 4 cases of FSD, 3 males and 1 female, aged 3 years and 3 months to 6 years (median age, 3 years and 4 months). The clinical manifestations were abnormal liver function and abnormal blood coagulation function, for which 2 cases had family genetic history. Liver biopsies revealed that, besides liver steatosis, fibrosis and inflammation, there were single or multiple eosinophilic inclusion bodies of various sizes and surrounding transparent pale halo in hepatocytes. Immunohistochemistry showed that the inclusion bodies were positive for anti-fibrinogen. Under the electron microscope, they corresponded to the dilated cisternae of the rough endoplasmic reticulum, which were occupied by compactly packed tubular structures and arranged into a fingerprint-like pattern with curved bundles. Gene sequencing revealed that the 2 cases of FGG mutation were located in exon 8 c.1106A>G (p.His369Arg) and c.905T>C (p.Leu302Pro), and 1 case was located in exon 9 c.1201C>T (p.Arg401Trp). No pathogenic variant was detected in the other case. Conclusions: FSD is a rare genetic metabolic disease and clinically manifests as abnormal liver function with hypofibrinogenemia. In the background of liver steatosis, fibrosis and inflammation, there are eosinophilic inclusions with pale halo in the hepatocytic cytoplasm, which can be identified by anti-fibrinogen immunohistochemical staining. The fingerprint-like structures under electron microscope are helpful for the diagnosis, while FGG sequencing detects the pathogenic mutation of exon 8 or 9 that can clearly explain the phenotype. However, the diagnosis of FSD cannot be completely ruled out if the relevant mutations are not detected.


5-Fluorouracil, doxorubicin, and mitomycin-C in the treatment of adenocarcinoma and large cell carcinoma of the lung.
Fifty-four patients with adenocarcinoma and large cell carcinoma of the lung, 16 with localized surgically resected disease and 38 with metastatic disease, were treated with 5-fluorouracil, doxorubicin, and mitomycin-C (FAM), in an attempt to prolong previously reported survival times in the patients. The postsurgical patients were given elective chemotherapy. Eighteen received radiation therapy for control of local disease. Tumor regression, attributable to chemotherapy alone, was noted in ten of 20 cases in whom there was measurable disease. The median survival time of all patients was 32 weeks, ranging from 25 weeks in those with distant metastases to 56 weeks in patients with surgically resected disease. FAM did not seem to produce any beneficial survival advantages.


The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, best characterized by the formation of proliferative nodules that express smooth muscle and melanocytic antigens within the lung parenchyma, leading to progressive destruction of lung tissue and function. The pathological basis of LAM is associated with Tuberous Sclerosis Complex (TSC), a multi-system disorder marked by low-grade tumors in the brain, kidneys, heart, eyes, lung and skin, arising from inherited or spontaneous germ-line mutations in either of the TSC1 or TSC2 genes. LAM can develop either in a patient with TSC (TSC-LAM) or spontaneously (S-LAM), and it is clear that the majority of LAM lesions of both forms are characterized by an inactivating mutation in either TSC1 or TSC2, as in TSC. Despite this genetic commonality, there is considerable heterogeneity in the tumor spectrum of TSC and LAM patients, the basis for which is currently unknown. There is extensive clinical evidence to suggest that the cell of origin for LAM, as well as many of the TSC-associated tumors, is a neural crest cell, a highly migratory cell type with extensive multi-lineage potential. Here we explore the hypothesis that the types of tumors that develop and the tissues that are affected in TSC and LAM are dictated by the developmental timing of TSC gene mutations, which determines the identities of the affected cell types and the size of downstream populations that acquire a mutation. We further discuss the evidence to support a neural crest origin for LAM and TSC tumors, and propose approaches for generating humanized models of TSC and LAM that will allow cell of origin theories to be experimentally tested. Identifying the cell of origin and developing appropriate humanized models is necessary to truly understand LAM and TSC pathology and to establish effective and long-lasting therapeutic approaches for these patients.


Idiopathic benign breast calcification.
A 56-year-old woman who came in for screening mammography was found to have extensive unilateral calcification of her left breast which had developed since her previous screening mammogram. The calcification had a ductal and lobular appearance. Possible known etiologies are discussed, but these do not explain the appearance in this case, implying that the cause is idiopathic.


From Detection to Resection: Photoacoustic Tomography and Surgery Guidance with Indocyanine Green Loaded Gold Nanorod@liposome Core-Shell Nanoparticles in Liver Cancer.
Conventional imaging methods encounter challenges in diagnosing liver cancer that is less than 10 mm or without typical hypervascular features. With deep penetration and high spatial resolution imaging capability, the emerging photoacoustic tomography may offer better diagnostic efficacy for noninvasive liver cancer detection. Moreover, near-infrared fluorescence imaging-guided hepatectomy was proven to be able to identify nodules at the millimeter level. Thus, suitable photoacoustic and fluorescence dual-modality imaging probe may benefit patients in early diagnosis and complete resection. In this study, we fabricated indocyanine green loaded gold nanorod@liposome core-shell nanoparticles (Au@liposome-ICG) to integrate both imaging strategies. These nanoparticles exhibit superior biocompatibility, high stability, and enhanced dual-model imaging signals. Next, we explored their effectiveness of tumor detection and surgery guidance in orthotopic liver cancer mouse models. Histological analysis confirmed the accuracy of the probe in liver cancer detection and resection. This novel dual-modality nanoprobe holds promise for early diagnosis and better surgical outcome of liver cancer and has great potential for clinical translation.


Immune reactive measles virus polypeptides on the cell's surface: turnover and relationship of the glycoproteins to each other and to HLA determinants.
To better understand the mechanism(s) whereby antibody and complement and cytotoxic lymphocytes lyse infected cells, we studied the structure, interrelationship and turnover of measles virus polypeptides expressed on the cell's surface. Of the 6 major viral structural polypeptides, L, HA, P, NC, F, and M, found in purified virions or infected cells, only 2, the HA and F, resided on the surface of infected cells. The HA was present primarily in the form of a 160k dimer, and F was identified as a 64k polypeptide migrating distinct from other viral polypeptides. With reduction, the HA migrated as a 80k monomer, and F0, after cleavage, was found to be composed of a 42k nonglycosylated polypeptide, F1, and a 24k glycosylated protein, F2. The relationship between F0 and F1 and between the HA dimer and monomer was verified by tryptic peptide mapping. The turnover of HA and F from the cell's surface was 10 and 9 hr, respectively. However, in the presence of specific antibody after a marked loss of viral antigen from the surface, the turnover for HA and F was 15 and 12 hr, respectively. Despite being independent molecules, HA and F were closely linked, as they moved together (co-capped) over the plasma membrane when incubated with monospecific or monoclonal antibody. In contrast, neither HA nor F co-capped with the major histocompatibility antigens or with other host cell proteins, which indicates a separation between these host cell proteins and measles viral glycoproteins on the cell's surface.


The Effect of Volunteering at a Student-Run Free Healthcare Clinic on Medical Students' Self-Efficacy, Comfortableness, Attitude, and Interest in Working with the Underserved Population and Interest in Primary Care.
The number of primary care physicians in the United States continues to lag behind the number of uninsured people. There has been a growing demand for medical students to improve their self-efficacy, comfortableness, attitude, and interest in working with the underserved and in primary care. This study aims to discern whether volunteering at a student-run, free healthcare clinic has a positive impact on these five variables of interest or not. A 95-item survey was distributed through Qualtrics Survey Software (Qualtrics, Provo, UT, USA) to medical students from the Class of 2018 and Class of 2019 at the University of Central Florida College of Medicine. They were recruited via emails, Facebook, and in-classroom announcements. Mean responses on a Likert-like scale to different survey items were collected and compared between two study cohorts: Keeping Neighbors In Good Health Through Service (KNIGHTS) Clinic volunteers and non-volunteers. Results from 128 students showed no significant differences in the means between the two cohorts (p-values were not significant). When volunteers were asked the survey item, "KNIGHTS Clinic positively influenced my attitude towards working with underserved patients," 62% strongly agreed, 26% agreed, 10% were neutral, and 2% disagreed. Based on the results, volunteering at KNIGHTS Clinic may not have a positive impact on the five variables of interest. However, the lack of significance may also be due to certain limitations of this study addressed elsewhere in this paper. With the majority of KNIGHTS Clinic volunteers agreeing that "KNIGHTS Clinic positively influenced […their] attitude towards working with underserved patients," there may be a positive impact of volunteering on volunteers' attitude towards working with the underserved.


Modelling psychological responses to the Great East Japan earthquake and nuclear incident.
The Great East Japan (Tōhoku/Kanto) earthquake of March 2011 was followed by a major tsunami and nuclear incident. Several previous studies have suggested a number of psychological responses to such disasters. However, few previous studies have modelled individual differences in the risk perceptions of major events, or the implications of these perceptions for relevant behaviours. We conducted a survey specifically examining responses to the Great Japan earthquake and nuclear incident, with data collected 11-13 weeks following these events. 844 young respondents completed a questionnaire in three regions of Japan; Miyagi (close to the earthquake and leaking nuclear plants), Tokyo/Chiba (approximately 220 km from the nuclear plants), and Western Japan (Yamaguchi and Nagasaki, some 1000 km from the plants). Results indicated significant regional differences in risk perception, with greater concern over earthquake risks in Tokyo than in Miyagi or Western Japan. Structural equation analyses showed that shared normative concerns about earthquake and nuclear risks, conservation values, lack of trust in governmental advice about the nuclear hazard, and poor personal control over the nuclear incident were positively correlated with perceived earthquake and nuclear risks. These risk perceptions further predicted specific outcomes (e.g. modifying homes, avoiding going outside, contemplating leaving Japan). The strength and significance of these pathways varied by region. Mental health and practical implications of these findings are discussed in the light of the continuing uncertainties in Japan following the March 2011 events.


Proteome-wide profiling of protein lysine acetylation in Aspergillus flavus.
Protein lysine acetylation is a prevalent post-translational modification that plays pivotal roles in various biological processes in both prokaryotes and eukaryotes. Aspergillus flavus, as an aflatoxin-producing fungus, has attracted tremendous attention due to its health impact on agricultural commodities. Here, we performed the first lysine-acetylome mapping in this filamentous fungus using immune-affinity-based purification integrated with high-resolution mass spectrometry. Overall, we identified 1383 lysine-acetylation sites in 652 acetylated proteins, which account for 5.18% of the total proteins in A. flavus. According to bioinformatics analysis, the acetylated proteins are involved in various cellular processes involving the ribosome, carbon metabolism, antibiotic biosynthesis, secondary metabolites, and the citrate cycle and are distributed in diverse subcellular locations. Additionally, we demonstrated for the first time the acetylation of fatty acid synthase α and β encoded by aflA and aflB involved in the aflatoxin-biosynthesis pathway (cluster 54), as well as backbone enzymes from secondary metabolite clusters 20 and 21 encoded by AFLA_062860 and AFLA_064240, suggesting important roles for acetylation associated with these processes. Our findings illustrating abundant lysine acetylation in A. flavus expand our understanding of the fungal acetylome and provided insight into the regulatory roles of acetylation in secondary metabolism.


Anthropometric Analysis of Cephalofacial Dimensions in Kerman, Iran.
The human body dimensions are affected by ecological, biological, geographical, racial, sex, and age factors. Craniofacial measurements can be considered to be one of the important tools for determination of the morphological characteristics of the head and face. In this study, which was conducted on Persian adolescents living in Kerman/Iran, different forms of head and face were determined for using in various aspects of medicine. The study was conducted on 732 participants including 366 males and 366 females in the age of 18-20-year-old. In addition to the height and weight of the participants, cephalofacial sizes of them were measured and then cephalic, facial, and brain indices were calculated. Among the cephalofacial sizes, cranial length and breadth, cranial circumference, prosopic length and prosopic breadth were significantly greater in males compared to females (P<0.005). Also, volume and weight of brain were significantly greater in male comparing to female participants (P<0.005). The predominant type of head was meso-cephal, and the predominant type of face was meso-prosopic in both sexes.


Survival and risk factors related to death in outpatients with cirrhosis treated in a clinic in Southern Brazil.
Cirrhosis represents a public health issue that generally evolves and presents serious complications. To assess the outcomes of outpatients with cirrhosis. We used a retrospective outpatient-based cohort, assessing 527 patients with cirrhosis. Demographic, clinical, and laboratory variables were analyzed, as well as the risk factors related to death, using the Cox proportional-hazard regression model. The Kaplan-Meier method was used to analyze survival rates. Patients had a mean age of 52.9±9.7 years and were more frequently men (59%), presenting Child-Turcotte-Pugh B or C in 43% of the cases in addition to a mean Model for End-Stage Liver Disease score of 12.0±4.1. The predominant etiology of liver disease was the hepatitis C virus. The most frequent complications during follow-up were ascites (34%), hepatic encephalopathy (17%), and hepatocellular carcinoma (17%). The survival rate at years 5 and 10 was 73 and 57%, respectively. The main risk factors that were related to death were, in a multivariate analysis, hepatitis C virus etiology, presence of hepatocellular carcinoma, and serum levels of albumin. Patients with cirrhosis monitored on an outpatient basis, despite showing a reasonable survival rate, have a worse prognosis when the etiology of liver disease is related to hepatitis C virus and when they have hepatocellular carcinoma or hypoalbuminemia.


Mechanisms of Reactions between HOI and HY (Y = Cl, Br, I) on a Water Nanodroplet Surface.
Iodine chemistry has a broad range of implications for atmospheric processes including new particle formation. Hypoiodous acid (HOI) is a major iodine reservoir species. Its heterogeneous recycling in marine aerosols influences the lifetime of ozone in the troposphere. One important step of such recycling is the reaction between HOI and HY (Y = Cl, Br, I). In this article, we employ ab initio molecular dynamics (AIMD) and quantum chemistry to investigate these reactions at the surface of atmospheric aerosols. Di-halogen (XY) can be formed in a picosecond time scale, with the formation of a loop structure connected by hydrogen and halogen bonds. The photolysis of XY at the surface of an aerosol is faster than in the gas phase. In addition to the formation of di-halogen, a new pathway to forming a [H2O···I···OH2]+ complex by the direct or indirect proton transition is identified. Results presented in this study deepen our understanding of the faster iodine-heterogeneous recycling at the surface of aerosols.


Imaging intratumor heterogeneity: role in therapy response, resistance, and clinical outcome.
Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care.


Protein kinase Cepsilon is linked to 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-alpha ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase Cepsilon transgenic mice.
Protein kinase Cepsilon (PKCepsilon), a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the PKC isoforms expressed in mouse epidermis. We reported that FVB/N transgenic mice that overexpress ( approximately 18-fold) PKCepsilon protein in basal epidermal cells and cells of the hair follicle develop papilloma-independent metastatic squamous cell carcinoma (mSCC) elicited by 7,12-dimethylbenz(a)anthracene-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion protocol. We now present that PKCepsilon transgenic mice elicit elevated serum tumor necrosis factor (TNF)alpha levels during skin tumor promotion by TPA, and this increase may be linked to the development of mSCC. A single topical application of TPA (5 nmol) to the skin, as early as 2.5 h after treatment, resulted in a significant (P < 0.01) increase (2-fold) in epidermal TNFalpha and more than a 6-fold increase in ectodomain shedding of TNFalpha into the serum of PKCepsilon transgenic mice relative to their wild-type littermates. Furthermore, this TPA-stimulated TNFalpha shedding was proportional to the level of expression of PKCepsilon in the epidermis. Using the TNF-alpha converting enzyme (TACE) inhibitor, TAPI-1, TPA-stimulated TNFalpha shedding could be completely prevented in PKCepsilon transgenic mice and isolated keratinocytes. These results indicate that PKCepsilon signal transduction pathways to TPA-stimulated TNFalpha ectodomain shedding are mediated by TACE, a transmembrane metalloprotease. Using the superoxide dismutase mimetic CuDIPs and the glutathione reductase mimetic ebselen, TPA-stimulated TNFalpha shedding from PKCepsilon transgenic mice could be completely attenuated, implying the role of reactive oxygen species. Finally, i.p. injection of a TNFalpha synthesis inhibitor, pentoxifylline, during skin tumor promotion completely prevented the development of mSCC in PKCepsilon transgenic mice. Taken together, these results indicate that: (a) PKCepsilon activation is an initial signal in TPA-induced shedding of TNFalpha from epidermal keratinocytes; (b) PKCepsilon-mediated signals to TACE are possibly mediated through reactive oxygen species; and (c) TPA-induced TNFalpha shedding may play a role in the development of mSCC in PKCepsilon transgenic mice.


Whey protein lycosome formulation improves vascular functions and plasma lipids with reduction of markers of inflammation and oxidative stress in prehypertension.
Parameters reflecting cardiovascular health and inflammation were studied in a pilot clinical trial conducted on 40 patients with prehypertension. The patients were treated with a new proprietary formulation of a whey protein (WP) isolate embedded into lycopene micelles (WPL) during a 1-month period. Control groups received lycopene or WP as a singular formulation or placebo pills for the same period of time. Combined WPL formulation of whey protein and lycopene has caused multiple favorable changes in the cardiovascular function (including a tendency to the reduced systemic blood pressure), the plasma lipid profile, and the inflammatory status of patients with prehypertension, whereas singular formulations of the compounds and placebo did not have such an effect. The reduction of plasma triglycerides and cholesterol fractions and almost two-fold decline in C-reactive protein (CRP) and inflammatory oxidative damage (IOD) levels as well as an increase in nitric oxide (NO), tissue oxygenation (StO(2)), and flow-mediated dilation values constitute the most significant benefit/outcome of the treatment with the combined formulation of whey protein and lycopene. The treatment did not affect the values of ankle-brachial index (ABI), body weight, and body mass index (BMI).


Swallowing, urine flow, and amniotic fluid volume responses to prolonged hypoxia in the ovine fetus.
Four days of hypoxia produce an extensive fetal polyuria with little change in amniotic fluid volume in the ovine fetus. We hypothesized that fetal swallowing and intramembranous absorption would increase with prolonged hypoxia to offset the polyuria. After a 24-hour normoxic period, nine ovine fetuses were subjected to 4 days of hypoxia induced by lowering maternal inspired oxygen content. Seven fetuses were monitored for 5 days as normoxic time controls. Measurements included fetal swallowed volume by a computerized system with Transonic flow probes, urine production by gravity drainage, and amniotic fluid volume by an indicator dilution technique. Data were averaged over 12-hour intervals, and a three-factor repeated-measures analysis of variance was used for statistical testing. During days 2 to 5, arterial oxygen tension was 20.7+/-1.1 (SE) mm Hg in the normoxic and 13.9+/-0.8 mm Hg in the hypoxic fetuses (P<.0001). Urine flow was unchanged over time in the normoxic fetuses and increased gradually from 693+/-88 to 2189+/-679 mL per day during hypoxia (P<.0001). The prehypoxia swallowed volume was similar in the two groups, averaging 447+/-95 mL per day. Although transiently decreased in eight of nine hypoxic fetuses, the 12-hour average swallowed volumes were not significantly different at any time in the hypoxic versus normoxic fetuses (P=.62). Amniotic fluid volume increased in the hypoxic fetuses relative to that in the normoxic fetuses (520+/-338 mL vs -226+/-136 mL, P<.01), although the increase was small (P<.01) relative to the excess volume of urine (4269+/-1306 mL). Estimated intramembranous absorption increased from 209+/-95 mL per day during normoxia to average 1032+/-396 mL per day during hypoxia. The current study supports the concept that prolonged hypoxia produces a progressive fetal polyuria with relatively small changes in amniotic fluid volume. Concomitantly, hypoxia does not induce prolonged changes in fetal swallowing; rather, intramembranous absorption greatly increases, thereby preventing severe polyhydramnios.


The role of diffusion tensor imaging metrics in the discrimination between cerebellar medulloblastoma and brainstem glioma.
Differentiation between cerebellar medulloblastoma and brainstem glioma is necessary for certain clinical circumstances. We aimed to evaluate the function of diffusion tensor imaging (DTI) metrics in the differentiation between cerebellar medulloblastomas and brainstem gliomas in children. The institutional review board approved this prospective study. Brain magnetic resonance imaging (MRI), including DTI, was assessed in 40 patients, who were divided into two groups: a medulloblastoma group (group 1, n = 25) and a brainstem glioma group (group 2, n = 15). The Mann-Whitney U test was utilized to compare tumoral fractional anisotropy (FA) and diffusivity (MD) values and tumor-to-parenchyma ratios for these values (rFA and rMD, respectively) between the two groups. Receiver-operating characteristic (ROC) curve analysis and the Youden index were exploited to calculate the cutoff value, along with the area under the curve (AUC), sensitivity, and specificity. The FA value for medulloblastomas was significantly higher than that for brainstem gliomas (P < 0.05). In contrast, the MD and rMD values for medulloblastoma were significantly lower than those for brainstem gliomas (P < 0.05). A cutoff MD value of 0.97 was identified as the most effective factor for the differential diagnosis between medulloblastomas and brainstem gliomas, which reached a sensitivity of 96%, a specificity of 100%, and an AUC of 99.5%. DTI metrics play a significant role in the differentiation between medulloblastoma and brainstem glioma in pediatric patients.


Health Effects of Natural Antioxidants.
Free radicals are produced during metabolic processes in the human body and can lead to oxidative stress, cellular aging, and the development of various diseases [...].


Visible spectrum extended-focus optical coherence microscopy for label-free sub-cellular tomography.
We present a novel extended-focus optical coherence microscope (OCM) attaining 0.7 μm axial and 0.4 μm lateral resolution maintained over a depth of 40 μm, while preserving the advantages of Fourier domain OCM. Our system uses an ultra-broad spectrum from a supercontinuum laser source. As the spectrum spans from near-infrared to visible wavelengths (240 nm in bandwidth), we call the system visOCM. The combination of such a broad spectrum with a high-NA objective creates an almost isotropic 3D submicron resolution. We analyze the imaging performance of visOCM on microbead samples and demonstrate its image quality on cell cultures and ex-vivo brain tissue of both healthy and alzheimeric mice. In addition to neuronal cell bodies, fibers and plaques, visOCM imaging of brain tissue reveals fine vascular structures and sub-cellular features through its high spatial resolution. Sub-cellular structures were also observed in live cells and were further revealed through a protocol traditionally used for OCT angiography.


Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein.
Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed an increasing cytotoxic action, as evidenced by loss of cell adhesion, loss of cellular protein, morphological changes, and cell disintegration as well as by strongly enhanced troglitazone-mediated isoprostane 8-IP liberation (fivefold to sixfold). T may be used as a model to explore the thiazolidinediones' mechanism on oxidation in a more general aspect for treatment for T2DM, because T is not clinically available.


The changing American family.
The increase in single-parent families, step-families, maternal employment, and young children in substitute care are among several important changes in the American family in recent decades. Although it is not clear that these changes necessarily lead to negative outcomes in children, it is apparent that a variety of potential risks and challenges confront many families today. Pediatricians can play a valuable role by helping families to adjust and cope with certain difficulties, such as divorce. However, in other areas such as child care, changes in public policies and programs are needed to better support families to optimally nurture their children.


[Management of Infective Endocarditis with Neurological Complication].
Neurological complications in patients with infective endocarditis are frequent and mortality is higher in those with neurological complications than in those without. The spectrum of neurological complications includes cerebral infarction, intracranial hemorrhage, intracranial infectious aneurysm, transient ischemic attack (TIA), meningitis, encephalopathy and brain abscess. The appropriate timing of valve surgery following a cerebrovascular event remains controversial because cardiopulmonary bypass may exacerbate neurological deficits. Previous studies suggest delaying valve surgery for 2 to 4 weeks following embolic stroke and at least 4 weeks following hemorrhagic stroke however, urgent valve surgery may be needed depending on the hemodynamic state of the patient. In the event of intracranial infectious aneurysm, therapeutic management is not perfectly standardized. We retrospectively reviewed the surgical results of infective endocarditis patients with neurological complications. Current trends in surgical timing and therapeutic decision-making are discussed.


Khat Chewing and Clinical Conditions Determine the Epidemiology of Primary Drug Resistance Tuberculosis in Amhara Region of Ethiopia: A Multicenter Study.
Rifampicin and/or multidrug-resistant tuberculosis (RR/MDR-TB) remains an uncontrolled public health emergency that has been synergized by the recently increased person-to-person transmission in the community as primary RR/MDR-TB, which is defined as RR/MDR-TB in new TB patients with no prior exposure to anti-TB treatment for more than one month. This study aimed to measure the prevalence and associated factors of primary drug-resistance among drug-resistant tuberculosis patients, as evidenced by the Amhara region treatment initiating centers. An institutional-based multicenter cross-sectional study was conducted from September 2010 to December 2017, among 580 RR/MDR-TB patients on the second-line anti-TB drug in the Amhara regional state. Data were collected from patient charts and registration books using a standardized data abstraction sheet. The data were entered using Epi-data 188.8.131.52 and transferred to Stata 14 software for further data management and analysis. A bivariable and multivariable binary logistic model was run subsequently, and finally, a p-value of less than 0.05 with a 95% confidence interval (CI) was used to declare the significance of the explanatory variable. The magnitude of primary drug resistance among drug-resistant tuberculosis patients was 15.69% (95% CI: 12.94, 18.89). Alcohol drinking (adjusted odds ratio [AOR] = 0.31, 95% CI: 0.12-0.82), khat chewing (AOR = 4.43; 95% CI: 1.67-11.76), ambulatory and bedridden functional status (AOR = 0.43; 95% CI: 0.24-0.76) and (AOR = 0.41; 95% CI: 0.19-0.91), respectively, positive sputum smear result (AOR = 0.48; 95% CI: 0.26-0.90), and HIV coinfection (AOR= 2.31; 95% CI: 1.31-4.06) remained statistically significant associated factors of primary RR/MDR-TB. Primary drug resistance is a public health problem in the study setting. Different behavioral and clinical conditions were significant factors of primary drug-resistant development. Mitigation strategies targeted on the patient's clinical condition, substance-related behaviors, and universal DST coverage might be very important for early detection and treatment of RR/MDR-TB to prevent community-level transmission.


Immunotherapy for house-dust mite allergy.
Since the discovery of house-dust mites (HDM) in the 1960's, allergy immunotherapy trials that used extracts of these mites have been conducted, first by subcutaneous (SCIT) and later by the sublingual (SLIT) route. When reviewed in 2013, published studies of HDM immunotherapy were found to often be characterized by small sample size, widely varying doses, and poorly defined disease severity and outcomes. These trials were thought to to support the efficacy of HDM subcutaneous allergy immunotherapy but the evidence for efficacy of sublingual immunotherapy was less firm. This report will review a large number of well-designed studies reported since 2013, mostly of SLIT, and in particular, of two newly developed HDM sublingual tablets. In addition, other aspects of HDM immunotherapy will be addressed, including use in atopic dermatitis, optimum duration of treatment, evidence for disease modification and use with adjuvants. Seventeen reports on 15 randomized, double-blind, placebo-controlled trials were identified as having been published since the cut-off date of the 2013 systematic review. Twelve of these reported results with the 2 HDM SLIT-tablets. These studies clearly established the appropriate doses and the efficacy and safety of these tablets in treating allergic rhinitis and asthma. Other reports offered support for use of HDM immunotherapy in selected patients with atopic dermatitis, for administration of HDM immunotherapy for 3 to 5 years, for anticipating disease modification after 3-5 years of treatment, and for the use of vitamin D and selected probiotics to enhance its efficacy. HDM SCIT and SLIT-tablet therapy have demonstrated effectiveness in allergic rhinitis and asthma. Appropriate dosing with HDM SLIT-liquid has not been established although a limited number of studies suggest it can be effective as well. HDM SCIT and HDM SLIT share efficacy in allergic rhinitis and asthma, disease modification and the duration of treatment required to produce persisting benefit.


OVERLAP OF THE BIREFRINGENT COMPONENT OF ADJACENT A REGIONS DURING THE INDUCED SHORTENING OF FIBRILS TEASED FROM DROSOPHILA MUSCLE.
Fibrils from the indirect flight muscle of Drosophila melanogaster which have been teased into a solution containing 0.1 M KCl, 2 mM EDTA, 4 mM MgCl(2), and 2.5 mM ATP at pH 7.0 can be made to shorten to 10 per cent of their initial length by reducing the level of ATP at a pH of about 8 or by briefly treating the fibrils with trypsin before lowering the level of ATP. Fibrils shortened in either of these ways, when dehydrated and immersed in nitrobenzene, display a strong positively birefringent band at the level of the Z band. In the trypsin-treated fibrils the width of this Z band increases as the fibril shortens. The data obtained are in agreement with the view that the positively birefringent Z band results from the interdigitation of A filaments in adjacent sarcomeres. With shortening to about 35 per cent of the initial length, the cytological pattern suggests that the A filaments of alternate as well as of adjacent A regions interdigitate.


Arthrocentesis For Temporomandibular Joint Pain Dysfunction Syndrome.
Temporomandibular joint (TMJ) dysfunction is painful condition of facial musculoskeletal system. Arthrocentesis is less invasive treatment of TMJ dysfunctions. It has been used to treat variety of TMJ disorders. The objective of this study was to determine the success of arthrocentesis in TMJPDS patients where conservative treatment had failed. This descriptive case study of 45 patients was completed in 6 months at Outpatient Department of Oral and Maxillofacial Surgery, Mayo hospital Lahore. TMJPDS Patients who were unresponsive to conservative treatment were included in this study. The study consisted of a single arthrocentesis procedure performed by a single oral surgeon per patient. Visual Analogue Scale was used to record pain while maximum mouth opening was measured by the interincisal distance in millimetres, at 1 month and 2 months after the treatment. Success was measured two months after arthrocentesis. Thirty (66.7%) patients had no pain and 15 (33.3%) patients had mild pain. Similarly, 16 (35.5%) patients had maximum mouth opening more than 30mm and 29 (64.5%) patients had less than 30 mm mouth opening, two months after arthrocentesis procedure. Arthrocentesis is very effective in patients suffering from TMPDS by reducing pain and discomfort and increase in mouth opening. This procedure should be considered in TMPDS patients who do not respond to conservative treatment.


[Design, synthesis and antitumor activity of sorafenib analogues containing 2-picolinylhydrazide moiety].
A novel series of sorafenib analogs containing 2-picolinyl hydrazide moiety were designed and synthesized. In vitro, most of synthesized compounds have antiproliferation activity on MDA-MB-231, ACHN, HepG2, Mia-PaCa-2 and SW1990 cell lines tested by MTT assay. It is worth noting that the antitumor activities of compounds 2c, 2d and 2f are more potent than that of sorafenib on pancreatic cancer cells Mia-PaCa-2 and SW1990, and the activities of compounds 3f and 3g are 2-3 times than that of sorafenib on human hepatocellular carcinoma HepG2 cell line.


Redox States of Protein Cysteines in Pathways of Protein Turnover and Cytoskeleton Dynamics Are Changed with Aging and Reversed by Slc7a11 Restoration in Mouse Lung Fibroblasts.
Slc7a11 is the key component of system Xc -, an antiporter that imports cystine (CySS) and exports glutamate. It plays an important role in cellular defense against oxidative stress because cysteine (Cys), reduced from CySS, is used for and limits the synthesis of glutathione (GSH). We have shown that downregulation of Slc7a11 is responsible for oxidation of extracellular Cys/CySS redox potential in lung fibroblasts from old mice. However, how age-related change of Slc7a11 expression affects the intracellular redox environment of mouse lung fibroblasts remains unexplored. The purpose of this study is to evaluate the effects of aging on the redox states of intracellular proteins and to examine whether Slc7a11 contributes to the age-dependent effects. Iodoacetyl Tandem Mass Tags were used to differentially label reduced and oxidized forms of Cys residues in primary lung fibroblasts from young and old mice, as well as old fibroblasts transfected with Slc7a11. The ratio of oxidized/reduced forms (i.e., redox state) of a Cys residue was determined via multiplexed tandem mass spectrometry. Redox states of 151 proteins were different in old fibroblasts compared to young fibroblasts. Slc7a11 overexpression restored redox states of 104 (69%) of these proteins. Ingenuity Pathway Analysis (IPA) showed that age-dependent Slc7a11-responsive proteins were involved in pathways of protein translation initiation, ubiquitin-proteasome-mediated degradation, and integrin-cytoskeleton-associated signaling. Gene ontology analysis showed cell adhesion, protein translation, and organization of actin cytoskeleton were among the top enriched terms for biological process. Protein-protein interaction network demonstrated the interactions between components of the three enriched pathways predicted by IPA. Follow-up experiments confirmed that proteasome activity was lower in old cells than in young cells and that upregulation of Slc7a11 expression by sulforaphane restored this activity. This study finds that aging results in changes of redox states of proteins involved in protein turnover and cytoskeleton dynamics, and that upregulating Slc7a11 can partially restore the redox states of these proteins.


Analyzing the symptoms in colorectal and breast cancer patients with or without type 2 diabetes using EHR data.
This research extracted patient-reported symptoms from free-text EHR notes of colorectal and breast cancer patients and studied the correlation of the symptoms with comorbid type 2 diabetes, race, and smoking status. An NLP framework was developed first to use UMLS MetaMap to extract all symptom terms from the 366,398 EHR clinical notes of 1694 colorectal cancer (CRC) patients and 3458 breast cancer (BC) patients. Semantic analysis and clustering algorithms were then developed to categorize all the relevant symptoms into eight symptom clusters defined by seed terms. After all the relevant symptoms were extracted from the EHR clinical notes, the frequency of the symptoms reported from colorectal cancer (CRC) and breast cancer (BC) patients over three time-periods post-chemotherapy was calculated. Logistic regression (LR) was performed with each symptom cluster as the response variable while controlling for diabetes, race, and smoking status. The results show that the CRC and BC patients with Type 2 Diabetes (T2D) were more likely to report symptoms than CRC and BC without T2D over three time-periods in the cancer trajectory. We also found that current smokers were more likely to report anxiety (CRC, BC), neuropathic symptoms (CRC, BC), anxiety (BC), and depression (BC) than non-smokers.


Necrotising enterocolitis after supraventricular tachycardia: an unusual precursor to a common problem.
Supraventricular tachycardia (SVT) is the most common neonatal arrhythmia. Necrotising enterocolitis (NEC) is a disease with multifactorial aetiology, most common in preterm infants. There are three previous case reports in the literature of NEC following neonatal SVT. We present two cases of late preterm infants with NEC, characterised by pneumatosis on abdominal X-ray and ultrasound, following recurrent SVT without haemodynamic instability. The infants were successfully treated with antibiotic therapy and bowel rest.


Vascular endothelial growth factor levels do not predict efficacy of systemic adjuvant treatment as assessed in 1127 breast cancer patients.
The vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and has proven to be of prognostic value in patients with primary breast cancer. In this study we investigated whether VEGF is of predictive value with regard to the efficacy of adjuvant systemic therapy in primary invasive breast cancer. In 1127 tumors of patients with invasive breast cancer the cytosolic levels of VEGF were measured using a quantitative enzyme-linked immunosorbent assay. These patients were followed for a median follow-up time of 59 months (range 2-268 months) after primary surgery. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. The VEGF levels showed a positive correlation with age, menopausal status and tumor size. In addition, VEGF levels were inversely correlated with estrogen and progesterone receptor levels. A high VEGF level predicted an early relapse in the univariate relapse-free survival (RFS) analysis for all patients (P=0.010), but not in the multivariate analysis. Furthermore, there were no statistically significant interactions between the levels of VEGF and the use of adjuvant endocrine therapy or chemotherapy in the RFS analysis. We conclude that tumor levels of VEGF do not predict the efficacy of adjuvant endocrine therapy or chemotherapy in patients with primary breast cancer.


Hydrogen sulfide inhibits activity of three isoforms of recombinant nitric oxide synthase.
To clarify the presence of cross-talk between H(2)S and NO, we investigated effect of NaHS, an H(2)S donor, on activity of recombinant NO synthase (NOS) isoforms. Activity of all nNOS, iNOS and eNOS was inhibited by NaHS (IC(50): 0.13-0.21 mM). In contrast, Na(2)SO(3), L-cysteine and threo-1,4-dimercapto-2,3-butanediol, a reductant, exerted poor inhibition of NOS activity. Increasing concentrations of tetrahydrobiopterin (BH(4)) reversed the NaHS inhibition of nNOS and eNOS, but not iNOS. Our data thus demonstrate inhibition of three NOS isoforms by NaHS/H(2)S, and suggest involvement of interaction of NaHS/H(2)S with BH(4) in inhibition of nNOS and eNOS, but not iNOS.


The effect of camera location on observation-based posture estimation.
This study used the observation-based method showing images on computer to evaluate angle estimation errors of 8 body segments in 3 motion planes at up to 28 segment angles and 5 camera locations with respect to goniometric measurements. Thirty observers participated in evaluating segment angles. Forearm (9.9°) and thigh (9.5°) had smaller errors than hand (14.0°) and foot had the smallest error (8.7°) due to its narrow range of motion (ROM). Errors were small with camera locations perpendicular to motions in the planes, such as 90° camera location for the flexion and extension of arm (6.3°), forearm (7.9°), thigh (6.5°), and leg (8.1°) in the sagittal plane. Segments had small errors of 3.1°, 4.6°, and 3.8° at segment angles of -90°, 0° and 90°, respectively. Care should be taken when estimating angles by the observation-based method for a specific segment motion and viewing direction is suggested to be perpendicular to the motion plane. Some companies may not allow many cameras or have obstacles for working posture evaluation in the workplace. These study results can be a guideline on proper selection of the number of cameras and their locations for a specific segment and its motion of interest to reduce visual segment angle estimation errors.


Integrative management of nausea and vomiting.
Nausea and vomiting are common symptoms seen in general practice. This article provides a brief overview of some integrative therapies that have demonstrated benefit in the management of these symptoms, specifically nausea induced by pregnancy, chemotherapy and surgery.


Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides.
Microviridins are ribosomally synthesized tricyclic depsipeptides produced by different genera of cyanobacteria. The prevalence of the microviridin gene clusters and the natural diversity of microviridin precursor sequences are currently unknown. Screening of laboratory strains and field samples of the bloom-forming freshwater cyanobacterium Microcystis via PCR revealed global occurrence of the microviridin pathway and an unexpected natural variety. We could detect 15 new variants of the precursor gene mdnA encoding microviridin backbones that differ in up to 4 amino acid positions from known isoforms of the peptide. The survey not only provides insights into the versatility of the biosynthetic enzymes in a closely related group of cyanobacteria, but also facilitates the discovery and characterization of cryptic microviridin variants. This is demonstrated for microviridin L in Microcystis aeruginosa strain NIES843 and heterologously produced variants.


Bile salt deconjugation and cholesterol removal from media by Lactobacillus strains used as probiotics in chickens.
Bile salt deconjugation by Lactobacillus strains is often closely linked to bile tolerance and survival of the strains in the gut and lowering of cholesterol in the host. The present study investigated the deconjugation of bile salts and removal of cholesterol by 12 Lactobacillus strains in vitro. The 12 strains were previously isolated from the gastrointestinal tract of chickens. The 12 Lactobacillus strains could deconjugate sodium glycocholate (GCA, 16.87-100%) and sodium taurocholate (TCA, 1.69-57.43%) bile salts to varying degrees, with all strains except L. salivarius I 24 having a higher affinity for GCA. The 12 Lactobacillus strains also showed significant (P < 0.05) differences in their ability to remove cholesterol from the growth medium (26.74-85.41%). Significant (P < 0.05) correlations were observed between cholesterol removal and deconjugation of TCA (r = 0.83) among the L. reuteri strains (C1, C10 and C16) and between cholesterol removal and deconjugation of TCA (r = 0.38) and GCA (r = 0.70) among the L. brevis strains (I 12, I 23, I 25, I 211 and I 218). In contrast, although L. gallinarum I 16 and I 26 and L. panis C 17 showed high deconjugating activity, there was no correlation between cholesterol removal and deconjugation of bile salts in these strains. The results showed that the 12 Lactobacillus strains were able to deconjugate bile salts and remove cholesterol in vitro, but not all strains with high deconjugating activity removed cholesterol effectively.


Gcse, a novel germ-cell-specific gene, is differentially expressed during meiosis and gametogenesis.
Gametogenesis is a complex process wherein germ cells develop from primordial diploid cells into haploid gametes. To understand the mechanisms controlling gametogenesis, we identified a novel germ-cell-specific gene, Gcse. Gcse produces two major transcripts that are 1589 bp (Gcse-l) and 906 bp (Gcse-s) in length. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) analyses of multiple tissues reveal that Gcse-l is expressed in both adult testes and ovaries, but Gcse-s is expressed only in adult testes. During female gonad development, Gcse-l is expressed from embryonic day 13.5 to adulthood, specifically in oocytes, and maintained in ovulated and fertilized eggs. However, Gcse-s signals were detected only in ovulated oocytes and fertilized eggs but not in adult ovary. During male gonad development, strong Gcse-l signals were detected in late pachytene spermatocytes and round spermatids. However, Gcse-s transcripts exist only in round spermatids. Furthermore, the expression of GCSE-L proteins and their subcellular localizations within cells are stage specific. GCSE-L is detected in the nucleus of late pachytene spermatocytes. During meiosis, GCSE-L is translocated to acrosome regions in spermatids and maintained in the acrosome of spermatozoa. GCSE-L colocalizes with acrosin and lectin peanut agglutinin in the Golgi apparatus. However, GCSE-S proteins are expressed only in the nucleus of spermatids. From these results, we suggest that GCSE proteins play roles in meiosis and may be involved in acrosome biogenesis during spermiogenesis.


Long-term hepatitis B infection in a scalable hepatic co-culture system.
Hepatitis B virus causes chronic infections in 250 million people worldwide. Chronic hepatitis B virus carriers are at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. A prophylactic vaccine exists and currently available antivirals can suppress but rarely cure chronic infections. The study of hepatitis B virus and development of curative antivirals are hampered by a scarcity of models that mimic infection in a physiologically relevant, cellular context. Here, we show that cell-culture and patient-derived hepatitis B virus can establish persistent infection for over 30 days in a self-assembling, primary hepatocyte co-culture system. Importantly, infection can be established without antiviral immune suppression, and susceptibility is not donor dependent. The platform is scalable to microwell formats, and we provide proof-of-concept for its use in testing entry inhibitors and antiviral compounds.The lack of models that mimic hepatitis B virus (HBV) infection in a physiologically relevant context has hampered drug development. Here, Winer et al. establish a self-assembling, primary hepatocyte co-culture system that can be infected with patient-derived HBV without further modifications.


Food Identity, Authenticity and Fraud: The Full Spectrum.
We are pleased to introduce this Special Issue of Foods dedicated to 'Food Identity, Authenticity and Fraud: The Full Spectrum'.[...].


Quantitation of diltiazem and desacetyldiltiazem in dog plasma by high-performance liquid chromatography.
A high-performance liquid chromatographic procedure was developed for the determination of diltiazem and desacetyldiltiazem in dog plasma. Two milliliters of plasma is extracted with a hexane-2-propanol mixture. The assay uses a reverse-phase column maintained at 55 degrees C with a silica saturation column and a pellicular precolumn. The mobile phase is acetonitrile-water (50:50) at pH 6.6 with 1.5-g/L heptanesulfonic acid added as the ion-pair reagent. The procedure is sensitive to 5 ng/mL for both compounds in dog plasma and is linear up to 2000 ng/mL for diltiazem and 1000 ng/mL for desacetyldiltiazem . Preliminary dog mean plasma profiles of diltiazem and desacetyldiltiazem are presented.


LayerPCM: An implicit scheme for dielectric screening from layered substrates.
We present LayerPCM, an extension of the polarizable-continuum model coupled to real-time time-dependent density-functional theory, for an efficient and accurate description of the electrostatic interactions between molecules and multilayered dielectric substrates on which they are physisorbed. The former are modeled quantum-mechanically, while the latter are treated as polarizable continua characterized by their dielectric constants. The proposed approach is purposely designed to simulate complex hybrid heterostructures with nano-engineered substrates including a stack of anisotropic layers. LayerPCM is suitable for describing the polarization-induced renormalization of frontier energy levels of the adsorbates in the static regime. Moreover, it can be reliably applied to simulating laser-induced ultrafast dynamics of molecules through the inclusion of electric fields generated by Fresnel-reflection at the substrate. Depending on the complexity of the underlying layer structure, such reflected fields can assume non-trivial shapes and profoundly affect the dynamics of the photo-excited charge carriers in the molecule. In particular, the interaction with the substrate can give rise to strong delayed fields, which lead to interference effects resembling those of multi-pulse-based spectroscopy. The robustness of the implementation and the above-mentioned features are demonstrated with a number of examples, ranging from intuitive models to realistic systems.


Kinetics of calcium binding to dental biofilm bacteria.
Dental biofilm bacteria can bind calcium ions and release them during a pH drop, which could decrease the driving force for dental demineralization (i.e. hydroxyapatite dissolution) occurring at reduced pHs. However, the kinetics of this binding and release is not completely understood. Here we validated a method to evaluate the kinetics of calcium binding and release to/from Streptococcus mutans, and estimated the importance of this reservoir as a source of ions. The kinetics of calcium binding was assessed by measuring the amount of bound calcium in S. mutans Ingbrit 1600 pellets treated with PIPES buffer, pH 7.0, containing 1 or 10 mM Ca; for the release kinetics, bacterial pellets previously treated with 1 mM or 10 mM Ca were exposed to the calcium-free or 1 mM Ca PIPES buffer, pH 7.0, for up to 60 min. Binding and release curves were constructed and parameters of kinetics were calculated. Also, calcium release was assessed by exposing pellets previously treated with calcium to a pH 5.0 buffer for 10 min. Calcium binding to bacteria was concentration-dependent and rapid, with maximum binding reached at 5 min. On the other hand, calcium release was slower, and according to the calculations, would never be complete in the groups pretreated with 10 mM Ca. Decreasing pH from 7.0 to 5.0 caused a release of calcium able to increase the surrounding fluid calcium concentration in 2 mM. The results suggest that dental biofilm bacteria may act as a calcium reservoir, rapidly binding ions from surrounding fluids, releasing them slowly at neutral pH and promptly during a pH drop.


Minocycline for Symptom Reduction During Oxaliplatin-Based Chemotherapy for Colorectal Cancer: A Phase II Randomized Clinical Trial.
The most debilitating symptoms during oxaliplatin-based chemotherapy in patients with colorectal cancer (CRC) are neuropathy and fatigue. Inflammation has been suggested to contribute to these symptoms, and the anti-inflammatory agent minocycline is safe and readily available. This proof-of-concept study investigated minocycline's capacity to reduce treatment-related neuropathy and fatigue and its impact on inflammatory markers during chemotherapy in a Phase II randomized, double-blind, placebo-controlled clinical trial. Patients with locally advanced or metastatic CRC who were scheduled for oxaliplatin-based chemotherapy were randomly assigned to receive either minocycline (100 mg twice daily) or placebo over four months from started chemotherapy. Toxicity assessments and blood samples were prospectively collected monthly. The severity of fatigue and numbness/tingling was assessed weekly using the MD Anderson Symptom Inventory. The primary endpoint, area under the curve for numbness/tingling and fatigue over approximately four months, was compared between the two arms. Of 66 evaluable participants, 32 received minocycline and 34 placebo. There was no observed significant symptom reduction on both fatigue and numbness/tingling in either arm, nor was there a difference in levels of serum proinflammatory and anti-inflammatory markers between arms. No Grade 3 adverse events nor disparity mediating effects on intervention were observed. Minocycline treatment is feasible and has a low-toxicity profile. However, with 200 mg/day, it did not reduce numbness/tingling or fatigue nor moderate inflammatory biomarkers from this Phase II randomized study. Our results do not support further exploration of minocycline for fatigue or neuropathy symptom intervention in patients treated for CRC.


Pseudomonas aeruginosa quorum sensing molecule N-3-oxo-dodecanoyl-l-homoserine lactone activates human platelets through intracellular calcium-mediated ROS generation.
Pseudomonas aeruginosa, an opportunistic pathogen release N-3-oxo-dodecanoyl-l-homoserine lactone (3-oxo-C12HSL) and N-butyryl-l-homoserine lactone (C4-HSL) quorum sensing (QS) molecules to regulate various virulence factors responsible for infection in the host. 3-oxo-C12 HSL not only regulates the bacterial gene expression but also modulates the host cell system. Thus, it is pertinent to evaluate the effect of these QS molecules on blood platelets which is responsible for the maintenance of hemostasis and thrombus formation. Here, in the present study, we showed that 3-oxo-C12 HSL activates platelets in a dose-dependent manner and induces intracellular calcium-mediated reactive oxygen species (ROS) release, whereas no such effect was observed with C4-HSL. 3-oxo-C12 HSL stimulated ROS release was mediated by NADPH oxidase. Results confirmed the involvement of phospholipase C (PLC) and IP3 receptor behind intracellular calcium-mediated ROS generation. The impact of 3-oxo-C12 HSL on platelet activation suggests that it could interfere and alter the normal function of platelet in individuals infected with P. aeruginosa.


Intake and health effects of thallium among a population living in the vicinity of a cement plant emitting thallium containing dust.
In order to assess the degree of thallium exposure in a population living around a thallium emitting cement plant in a small city in North-West Germany thallium levels in 24 h urine samples of 1,265 subjects and in hair samples of 1,163 subjects were determined. Urinary thallium levels in two groups of subjects living in an urban and a rural area of West Germany were determined for reference. As compared to these subjects the population living around the cement plant exhibited obvious signs of increased thallium intake. The mean urinary thallium concentration was 2.6 micrograms/l and ranged up to 76.5 micrograms/l. In contrast, the mean urinary thallium levels of the two reference groups were 0.2 and 0.4 micrograms/l, respectively. Hair thallium levels of the population living around the cement plant were also markedly increased (mean: 9.5 ng/g). The major route of the population's increased intake of thallium was found to be the consumption of vegetables and fruit grown in private gardens in the vicinity of the cement plant. As was shown by chemical analyses vegetables and fruit grown in these gardens were contaminated by thallium-containing atmospheric dust fall-out caused by emissions of the cement plant. The pulmonary route of uptake as well as other sources did not seem to play a significant role in the population's exposure to thallium. Polyneuritic symptoms, sleep disorders, headache, fatigue and other signs of psychasthenia were found to be the major health effects associated with increased thallium levels in urine and hair. No positive correlation was found between the thallium levels in hair and urine and the prevalence of skin alterations, hair-loss and gastro-intestinal dysfunctions.


Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice.
Cholestasis promotes endoplasmic reticulum (ER) stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice. ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2) cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma. Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette [Abc]b11) and a bile salt efflux pump (Abcc3). The observed regulation of Cyp7a1, Abcb11, and Abcc3 occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice. Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism.


[Changes of scavenger receptor class B type I and peroxisome proliferator-activated receptor gamma expression in atherosclerotic mini swine].
To study the expressions of scavenger receptor class B type I(SR-BI) and peroxisome proliferator-activated receptor gamma (PPARgamma) in atherosclerotic mini swine and provide a new mechanism for investigating the pathogenesis of atherosclerosis. Chinese mini swine were fed by a normal control diet or a high fat/high cholesterol diet for 12 months after common carotid artery injury induced by balloon denudation. Plasma total cholesterol(TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were determined by commercially enzymatic methods every two months. The sections, which were taken from liver and abdominal aorta, were stained with hematoxylin eosin. The expressions of SR-BI and PPARgamma mRNA and protein in liver and aorta tissue were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry respectively. At the end of 12 months, plasma TC, HDL-C and TG in HFHC mini swine were increased. There were fatty liver and atherosclerotic plaque in mini swine live and aorta respectively. The expression of SR-BI was upregulated in HFHC mini swine liver and aorta tissue. HFHC may induce atherosclerosis and the expression of SR-BI and PPARgamma. Upregulating SR-BI expression may inhibit atherosclerosis. Increasing SR-BI expression in liver and aorta may accelerate SR-BI-mediated reverse cholesterol transport and develop a new anti-atherogenic strategy.


Small-molecule inhibitors of spleen tyrosine kinase as therapeutic agents for immune disorders: will promise meet expectations?
Following on the heels of the US FDA approval of tofacitinib (Xeljanz, Pfizer, USA), an inhibitor of the JAK family members, and ibrutinib (Imbruvica, Janssen, Belgium), an inhibitor of BTK, for the treatment of rheumatoid arthritis and chronic lymphocytic leukemia, respectively, there is now renewed interest in the biopharmaceutical industry in the development of orally active small-molecule agents targeting key protein kinases implicated in immune regulation. One such 'immunokinase' target is SYK, a non-receptor tyrosine protein kinase critical for transducing intracellular signaling cascades for various immune recognition receptors, such as the B-cell receptor and the Fc receptor. Here, we review and discuss the progress and challenges in the development of small-molecule inhibitors of SYK and their potential as a new class of disease-modifying immunosuppressive agents for certain inflammatory and autoimmune disorders.


Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction.
Melorheostosis is a rare non-hereditary condition characterized by dense hyperostotic lesions with radiographic "dripping candle wax" appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi-method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal-like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi-layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: -4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro-CT, due to increased tissue vascularity and elevated 2D-microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano-indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research.


Occurrence, storage and release of neurotensin-like immunoreactivity from the adrenal gland.
In the present study we have investigated the presence of radioimmunoassayable neurotensin-like immunoreactivity (NTLI) in extracts of adrenal glands from hen, guinea-pig, rat, cat, dog and man. In addition, gel filtration chromatography and studies on the storage site of NTLI, using subcellular fractionation techniques, were performed. Finally, NTLI release in relation to noradrenaline (NA) from cat adrenal glands upon splanchnic nerve activation was studied in vivo. In all species investigated except guinea-pig and man, the NTLI levels in the adrenal glands were higher than the levels in the heart (control tissue) but lower than in the ileum. Gel filtration of NTLI from cat adrenal glands revealed presence of roughly equal amounts of the whole neurotensin molecule, i.e. NT(1-13), and its main metabolite the N-terminal octapeptide NT(1-8), while in plasma from the adrenal vein almost exclusively NT(1-13) was revealed after electrical stimulation of the splanchnic nerve. The release of NTLI and NA upon splanchnic stimulation was antagonized by hexamethonium. Subcellular fractionation of cat adrenal glands indicated that NTLI was stored in a large subcellular organelle, co-migrating with chromaffin granules. We suggest that NT may be a new adrenal gland hormone or transmitter, possibly co-stored with NA in chromaffin cells. However, at the present stage it cannot be distinguished whether NT exerts its actions locally within the adrenal gland or after release into the systemic circulation.