The estimation of fibrinogen levels in animal plasmas by a simple refractometric method. A comparison with a biuret method.
A comparison was made between a biuret (reference) method and a simple refractometric (test) method for measuring fibrinogen levels in 84 animal plasmas. Although the correlation between the two methods was high (4=0.90 P less than 0-001) there was considerable random variation in the refractometric results in relation to the biuret results. This was thought to be due in part to the fact that refractometric results could only be expressed in multiples of 2.4 g/litre. In spite of this limitation, the refractometric method, on the grounds of speen and simplicity, is considered to have worthwhile application for fibrinogen determinations in practice laboratory.


Immunoglobulin G4 (IgG4)-positive plasma cell infiltration is associated with the clinicopathologic traits and prognosis of pancreatic cancer after curative resection.
Interactions between pancreatic cancer cells and inflammatory cells play crucial roles in the biological behavior of pancreatic cancer. Abundant infiltration of immunoglobulin G4 (IgG4)-positive plasma cells in the pancreas is the most significant feature of autoimmune pancreatitis; however, the clinical significance of IgG4-positive plasma cell infiltration in pancreatic cancer has not previously been reported. Herein, we analyzed intratumoral and peritumoral infiltrations of IgG4-positive plasma cells in 95 pancreatic cancer cases after curative resection. The correlations between IgG4-positive plasma cell infiltration and the clinicopathologic traits and overall survival of pancreatic cancer were investigated. IgG4-positive plasma cells were found in 86 % of tumor tissue samples compared with 69 % of peritumoral tissue samples (P = 0.0063). The high-level infiltration of intratumoral IgG4-positive plasma cells was positively correlated with poor histological grade (P = 0.017). The high-level infiltration of intratumoral IgG4-positive plasma cells was significantly correlated with worse prognosis (P = 0.01) in multivariate analysis. We further found that intratumoral M2-polarized tumor-associated macrophages (TAMs) were positively, linearly correlated with IgG4-positive plasma cells. In conclusion, IgG4-positive plasma cell infiltration is correlated with the clinicopathologic traits and overall survival of pancreatic cancer. High-level intratumoral infiltration of IgG4-positive plasma cells is an independent predictor for poor overall survival in pancreatic cancer patients after curative resection. Intratumoral M2-polarized TAMs probably induce IgG4-positive plasma cells.


Reaction-passivation mechanism driven materials separation for recycling of spent lithium-ion batteries.
Development of effective recycling strategies for cathode materials in spent lithium-ion batteries are highly desirable but remain significant challenges, among which facile separation of Al foil and active material layer of cathode makes up the first important step. Here, we propose a reaction-passivation driven mechanism for facile separation of Al foil and active material layer. Experimentally, >99.9% separation efficiency for Al foil and LiNi0.55Co0.15Mn0.3O2 layer is realized for a 102 Ah spent cell within 5 mins, and ultrathin, dense aluminum-phytic acid complex layer is in-situ formed on Al foil immediately after its contact with phytic acid, which suppresses continuous Al corrosion. Besides, the dissolution of transitional metal from LiNi0.55Co0.15Mn0.3O2 is negligible and good structural integrity of LiNi0.55Co0.15Mn0.3O2 is well-maintained during the processing. This work demonstrates a feasible approach for Al foil-active material layer separation of cathode and can promote the green and energy-saving battery recycling towards practical applications.


Quality Control of Magnetic Resonance Elastography Using Percent Measurable Liver Volume Estimation.
Although studies have described factors associated with failed magnetic resonance elastography (MRE), little is known about what factors influence usable elastography data. To identify factors that have a negative impact on percent measurable liver volume (pMLV), defined as the proportion of usable liver elastography data relative to the volume of imaged liver in patients undergoing MRE. Retrospective. A total of 264 patients (n = 132 males, n = 132 females; mean age = 57 years) with suspected or known chronic liver disease underwent MRE paired with a liver protocol MRI. MRE was performed on a single 1.5 T scanner using a two-dimensional gradient-recalled echo phase-contrast sequence with a passive acoustic driver overlying the right hemiliver. Stiffness maps (usable data at 95% confidence) and liver contours on magnitude images of the MRE acquisition were manually traced and used to assess mean stiffness and pMLV. Hepatic fat fraction and R2 * values were also calculated. The distance from the acoustic wave generator on the skin surface to the liver edge was measured. Two radiologists performed the MR analyses with 50 overlapping cases for inter-reader analysis. Linear regression was performed to identify factors significantly associated with pMLV. Intraclass correlation was performed for inter-reader reliability. pMLV was 31% ± 20% (range 0%-86%). Complete MRE failure (i.e. pMLV = 0%) occurred in 10 patients (4%). Multivariate linear regression identified higher hepatic fat fraction, R2 *, BMI, and driver-to-liver surface distance; male sex; and lower mean liver stiffness was significantly independently associated with lower pMLV. Intraclass correlation for pMLV was 0.96, suggestive of excellent reliability. Higher fat fraction, R2 *, BMI, driver-to-liver surface distance, male sex, and lower mean liver stiffness were associated with lower pMLV. Optimization of image acquisition parameters and driver placement may improve MRE quality, and pMLV likely serves as a diagnostic utility quality control metric. 3 TECHNICAL EFFICACY STAGE: 2.


Cellular targets and receptors for interleukin-6. II. Characterization of IL-6 binding and receptors in peripheral blood cells and macrophages.
Within 15 min, approximately 2.5% of 125I-labelled interleukin-6 (IL-6) injected intravenously into rats was taken up by the spleen. As determined by light microscopic autoradiography, uptake was mainly (60%) accounted for by macrophages in the red pulp. 125I-IL-6 binding in rat peritoneal macrophages was quantitatively similar to that in cultured human monocytes and T-cells. By comparison, IL-6 binding to polymorphonuclear granulocytes and freshly isolated monocytes was low. Stimulation with antigen, but not with mitogen (PWM), induced receptor presentation in B-cells, whereas antigen and mitogen downregulated the binding in T-cells. At 4 degrees C, labelled IL-6 bound to cells with a half-time of about 1.5 h. Binding appeared reversible, but dissociation was slow and incomplete. The apparent Kd for IL-6 binding was about 30 pmol l-1 in most cell types, however, values of approximately 120 pmol l-1 were obtained in polymorphonuclear granulocytes. At 37 degrees C, 125I-IL-6 was rapidly internalized by T-cells and monocyte-macrophages, and after a lag time, TCA-soluble radioactivity was released from the cells following a sigmoidal curve. Polyacrylamide gel electrophoresis of radiolabelled IL-6 cross-linked to its binding sites in T-cells, yielded receptor-ligand complexes with molar masses of 70-80 and 120-140 kg mol-1. This would agree with a dimeric conformation of the IL-6 receptor.


The tardigrade Dsup protein enhances radioresistance in Drosophila melanogaster and acts as an unspecific repressor of transcription.
The tardigrade-unique damage suppressor protein (Dsup) can protect DNA from ionizing radiation and reactive oxygen species (ROS). In this study, we generated Dsup-expressing lines of Drosophila melanogaster and demonstrated that Dsup increased the survival rate after γ-ray irradiation and hydrogen peroxide treatment in flies too, but reduced the level of their locomotor activity. The transcriptome analyses of Dsup-expressing lines revealed a significant number of DEGs, >99% of which were down-regulated. Moreover, Dsup could bind RNA. These findings suggest that Dsup can act not only as a DNA protector but also as a non-specific transcriptional repressor and RNA-binding protein, that may lead to disturbance of a number of biological processes in D. melanogaster. The obtained data demonstrate features of the Dsup protein action in non-tardigrade organisms and can be used to understand the impact of other unspecific DNA/RNA-binding proteins on ROS and radiation resistance, gene expression, and epigenetic processes.


Soluble CD21 induces activation and differentiation of human monocytes through binding to membrane CD23.
Interactions between CD23, the low-affinity receptor for IgE, and CD21, the C3d/EBV receptor, modulate several intracellular events in lymphocytes. A soluble form of CD21 (sCD21) corresponding to the extracellular domain of the receptor circulates in normal plasma. We now demonstrate that purified sCD21 acts as a functional ligand for CD23-expressing monocytes. Soluble CD21 induced an increase in intracellular cGMP levels and the production of IL-6 and TNF-alpha in IL-4-pretreated monocytes induced to express CD23 but not in unstimulated CD23- monocytes. The accumulation of cGMP and the production of TNF-alpha were inhibited by NG-monomethyl-L-arginine (L-NMMA), indicating that sCD21 activates the L-arginine pathway of NO production. We demonstrated that sCD21 activates NO synthase (NOS) since it was found to enhance the conversion of L-arginine into L-citrulline and induce the intracellular expression of inducible NOS in CD23+ monocytes. In addition, sCD21 was shown to up-regulate the expression of HLA-DR and CD40 and decrease that of CD14 on cultured CD23+ monocytes. Thus, in a fashion similar to IgE complexes, sCD21 is able to efficiently trigger CD23 signaling pathways, inducing the release of pro-inflammatory mediators by human monocytes. Soluble CD21 up-regulates the expression of molecules involved in antigen presentation, further suggesting a potential immunoregulatory function for the soluble molecule.


Authorities and procedures for licensing veterinary biological products in the United States.
The licensing procedures reviewed above provide a framework for the production of pure, safe, potent, and efficacious veterinary biological products. The licensing, inspection, and testing activities of the Veterinary Biologics program provide the oversight necessary to ensure the continued availability of high-quality veterinary biological products in the United States.


[Effect of N-phenylnaphthylenediamine on catecholamine distribution in peritoneal mast cells].
Histochemical fluorescent technique employed in the in vitro experiment detected stimulating effect of PND on the levels of catecholamines in peritoneal mast cells.


Nationwide dissemination of contingency management: the Veterans Administration initiative.
Contingency management (CM) is an empirically validated intervention but one not often applied in practice settings in the US. The aim of this article is to describe the Veterans Administration (VA) nationwide implementation of CM treatment. In 2011, the VA called for integration of CM in its intensive outpatient substance abuse treatment clinics. As part of this initiative, the VA funded training and ongoing implementation support, and it provided direct funds for reinforcers and other intervention costs. Over 100 clinics received this funding in 2011, and CM has been implemented in over 70 substance abuse treatment clinics since August 2011. This training and implementation experience has been highly successful and represents the largest scale training in evidence-based treatments for substance use disorders in the VA health care system to date. This program may serve as a model for training in evidence-based treatments.


Demographic profile, clinical and microbiological predictors of mortality amongst admitted pediatric TB patients in a tertiary referral tuberculosis hospital.
Pediatric tuberculosis (TB) constitutes 8% of the total caseload of TB. Children are particularly vulnerable to dissemination of disease and mortality. To determine mortality rate, elucidate type of TB, causes and predictors of mortality, if any, in admitted pediatric TB patients. Present retrospective study was conducted in a tertiary referral center over last 6½ year on children who died out of total TB admissions. Out of total 1380 pediatric (<15 years of age) TB admissions, 74 children died, a mortality rate of 5.36%. Mean age was 11.4 years with highest mortality 47 (63.51%) in patients from 11 to 14 years age group. Significant majority 58 (78.38%) patients were females (p < 0.011). Range of hospital stay was 0-113 days with 7 (9.5%), 9 (12.16%) and 27 (36.48%) children dying on day of admission, next day and 3rd-7th day respectively, therefore a total of 43 (58.11%) died within first week of admission. Most 60 (81.08%) patients belonged to poor socio-economic status. History of contact was present in 12 (16.22%) cases while none had diabetes. 31 (41.89%) patients had sepsis and severe anemia (Hb ≤ 6 g %) was present in 6 (8.11%) patients at admission, out of which 4 died on the same day of admission, even before blood could be arranged. Most patients 68 (91.89%) had pulmonary TB with 25 children having concomitant extrapulmonary involvement, while 4 (5.41%) had meningeal TB and 2 (2.70%) had disseminated TB with HIV. Microbiological confirmation was achieved in 51 (68.92%) (48 PTB and 3 EPTB) cases while 23 (31.08%) were clinically diagnosed. Bilateral extensive fibro-cavitary disease with infiltrations was the commonest. Drug resistance was confirmed in 21 (28.38%) with 2, 5, 8, 5 and 1 patient diagnosed with mono H, RR, MDR, pre-XDR and XDR respectively but results of 9 patients were received posthumously. Treatment given was category 1, category 2 and regimens for drug resistant TB in 24 (32.43%), 29 (39.19%) and 21 (28.37%) cases respectively based on prior history of ATT and drug sensitivity. Adverse drug reactions were noted in 12 (16.21%) cases. Noted immediate causes of mortality were cardio-respiratory failure, sudden pneumothorax, massive hemoptysis, sepsis, extensive pulmonary disease and aspiration pneumonia. The pointers towards mortality include female gender, severe malnutrition, anemia, extensive disseminated disease and drug resistant TB. Ignorance, dependency of children on parents, poor adherence and late referrals into the system lead to delayed diagnosis and initiation of proper regimen based treatment. Early referrals of non-responders and failures to centers equipped with programmatic management facilities are essential for proper, timely management of pediatric TB to reduce mortality.


Distribution, sources and chemical screening-level assessment of toxic metals in the northern Bay of Bengal, Bangladesh.
The present study aims to examine the distribution, sources and potential risks of toxic metals in the northern Bay of Bengal, Bangladesh. We found Cu, Pb, Zn and Hg exhibited similar spatial distribution pattern. Influenced by the Ganges-Brahmaputra River and the Karnafuli River, there were higher concentrations of these metals associated with the finer sediment and higher TOC in the northeastern portion of the study area. Moreover, coal transportation was assumed to account for the distinctive spatial distribution of As with higher concentration down the Port of Chittagong in the eastern boundary. Chemical-screening level assessment demonstrated the majority of the metals exceeded the threshold effect values, indicating certain possibility of adverse effect. The concentrations of Ni were higher than the possible hazardous values, suggesting high possibility of harmful consequences. The uncontaminated sediments mainly distributed in northwestern and the central portions affected by the delta erosion and marine transported sediments.


The role and mechanism of unfolded protein response signaling pathway in methylmercury-induced apoptosis of mouse spermatocytes germ cell-2 cells.
The study aimed to explore the role and mechanism of unfolded protein response (UPR) in methylmercury (MeHg)-induced Mouse Spermatocytes (GC-2spd[ts]) apoptosis. Methods such as MTT, flow cytometry, and Western Blot were used to evaluate the cell viability, membrane potential (MMP), reactive oxygen species (ROS), calcium ion (Ca2+ ), rate of cell apoptosis, and the expression of apoptosis-related and UPR-related protein. The results showed that with the increase of MeHg concentration, cell viability and MMP decreased, ROS, Ca2+ , rate of cell apoptosis, and the expression of apoptosis-related protein and UPR-related protein increased. To further explore the effect of ROS-induced oxidative damage on it, the ROS inhibitor N-acetyl-L-cysteine (NAC) was used. The effects of MeHg on germ cell (GC-2) cells were partially inhibited after NAC pretreatment. Our present study proved that MeHg might induce cell apoptosis by activating the UPR signaling pathway in GC-2 cells and affect normal reproductive function.


Estrogen and progesterone receptor profile patterns in primary breast cancer.
Estrogen (ER) and progesterone receptor (PgR) analyses have been performed in 884 primary, malignant human breast tumor biopsies. Receptor contents were evaluated with respect to age and menopausal status. The frequency of ER+ tumors was found to be significantly higher in postmenopausal than in pre/perimenopausal women. Age rather than menopausal status was found to be associated with this difference. The significant association with age was found in the post- but not the pre/perimenopausal women. The frequency of PgR+ tumors was found to be significantly lower in the postmenopausal than in the pre/perimenopausal women. Neither age nor menopausal status alone could account for this difference, which appears to be due to a compound effect of the two factors. The distribution of receptor profile patterns is described according to menopausal status. The patterns differ significantly in pre- and postmenopausal women. PgR dominates in the premenopausal tumor while ER dominates in the postmenopausal tumor. This difference is apparent within the subgroup of ER + PgR + patients as well. The current tenets for prediction of recurrent disease utilizing steroid hormone receptor determinations are discussed for the group of ER + PgR + patients.


Humoral and cellular immune response after severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccination in heart transplant recipients: An observational study in France.
Heart transplant (HT) recipients have a high risk of developing severe COVID-19. Immunoglobulin G antibodies are considered to provide protective immunity and T-cell activity is thought to confer protection from severe disease. However, data on T-cell response to mRNA vaccination in a context of HT remains limited. In 96 HT patients, a IFN-γ release assay and an anti-Spike antibody test were used to evaluate the ability of SARS-CoV-2 mRNA vaccines to generate cellular and humoral immune response. Blood samples were collected few weeks to 7 months after vaccination. Multiple fractional polynomial and LASSO regression models were used to define predictors of T-cell response. Three to five months after vaccination, three doses of vaccine induced a positive SARS-CoV-2 T-cell response in 47% of recipients and a positive humoral response in 83% of recipients, 11.1% of patients remained negative for both T and B cell responses. Three doses were necessary to reach high IgG response levels (>590 BAU/mL), which were obtained in a third of patients. Immunity was greatly amplified in the group who had three vaccine doses plus COVID-19 infection. Our study revealed that T and B immunity decreases over time, leading us to suggest the interest of a booster vaccination at 5 months after the third dose. Moreover, a close follow-up of immune response following vaccination is needed to ensure ongoing immune protection. We also found that significant predictors of higher cellular response were infection and active smoking, regardless of immunosuppressive treatment with mycophenolate mofetil (MMF).


Modified "liver-sparing" multivisceral transplant with preserved native spleen, pancreas, and duodenum: technique and long-term outcome.
Modification of the originally described multivisceral transplant operation was introduced at our institution 17 years ago. Donor liver was spared, and native spleen along with pancreaticoduodenal complex was preserved. Thirty-six modified multivisceral grafts that include stomach, duodenum, pancreas, and intestine were given to 30 adults and six children. Leading causes of intestinal failure were pseudo-obstruction and Gardner's syndrome. Native spleen was preserved in 24 (67%) recipients along with pancreaticoduodenal complex in 18 (50%). Immunosuppression was tacrolimus-based, and recipient preconditioning was utilized in 80% of patients. Patient survival was 94% at 1 year and 75% at 5 years with graft survival of 91% and 51%; respectively. With mean follow-up of 51 ± 35 months, full nutritional autonomy was achieved in 89% of current survivors with no single example of disease recurrence. Preservation of native spleen was associated with increased survival and reduced risk of PTLD, life-threatening infections, and GVHD with no significant impact on graft loss due to rejection. Concomitant preservation of pancreaticoduodenal complex eliminated risks of biliary complications and glucose intolerance. Modified multivisceral transplantation with and without preservation of native spleen, pancreas, and duodenum is a valid therapeutic option for patients with diffuse gastrointestinal disorders and preserved hepatic functions.


Understanding esophageal neurofibroma: A case series and systematic review.
Esophageal neurofibroma is a rare benign esophageal neoplasm. With very few cases documented in the literature, not much is known about the demographics and clinicopathologic features of this tumor. This study was aimed at presenting a case report of an esophageal neurofibroma, and to conduct a systematic review of published cases. This review was performed according to the PRISMA guidelines. Literature search was conducted through PubMed, SCOPUS, and Cochrane Databases from inception until May 2020 for all histologically confirmed cases of esophageal neurofibroma. 28 cases, including the newly reported case, were included in the review. The mean age at diagnosis was 53.3 years ±12.1. 53.6% were male. Dysphagia was the most common presenting symptom (53.6%). Most of the reported cases involved the upper esophagus (39.3%). The most utilized diagnostic test was esophagogastroduodenoscopy (57.1%). The mean tumor size was 6.1 cm ± 5.1. Preoperative biopsy was done for 9 cases, out of which seven were negative or inconclusive. In 17 cases (60.7%), immunohistochemical (IHC) staining of the resected tumor was not performed. S100 was the most utilized IHC stain. Enucleation (39.3%) was the most common treatment, followed by esophagectomy (28.6%). Esophageal neurofibroma should be considered in the setting of dysphagia caused by a subepithelial tumor. Accurate preoperative histologic diagnosis by using a well-defined biopsy algorithm, in conjunction with IHC analysis, will favor less aggressive surgical treatment and surveillance of asymptomatic lesions. Minimally invasive surgical treatment is feasible and should be considered when the expertise is available.


Isolated tumoral pyruvate dehydrogenase can synthesize acetoin which inhibits pyruvate oxidation as well as other aldehydes.
Oxidation of 1 mM pyruvate by Ehrlich and AS30-D tumor mitochondria is inhibited by acetoin, an unusual and important metabolite of pyruvate utilization by cancer cells, by acetaldehyde, methylglyoxal and excess pyruvate. The respiratory inhibition is reversed by other substrates added to pyruvate and also by 0.5 mM ATP. Kinetic properties of pyruvate dehydrogenase complex isolated from these tumor mitochondria have been studied. This complex appears to be able to synthesize acetoin from acetaldehyde plus pyruvate and is competitively inhibited by acetoin. The role of a new regulatory pattern for tumoral pyruvate dehydrogenase is presented.


Triphenylethylene antiestrogen binding sites (TABS) specificity.
The relative binding affinities (RBA) of various compounds for the triphenylethylene antiestrogen binding sites (TABS) were examined. The ability of tamoxifen to inhibit the binding of [3H]tamoxifen to salt extracted (0.4 M KCl) TABS from rat liver nuclei was used as a standard by which other compounds were compared (tamoxifen RBA, 100; Kd approximately 1 nM). Nafoxidine was the most effective triphenylethylene compound used (RBA 333; Kd approximately 0.3 nM) whereas the RBA of zuclomiphene and enclomiphene was not different from tamoxifen. MER-29 was the weakest inhibitor of the triphenylethylene derivatives (RBA 10; Kd approximately 10 nM). Trifluoperazine, chlorpromazine and the anti-calmodulin drugs W-13 and W-12 had RBA's of 25, 1, 1 and 0.1 respectively. The binding affinities of cholesterol and 7-ketocholesterol were significant (Kd approximately 22 nM) while the steroid hormones, estradiol, testosterone, progesterone and corticosterone displayed not observable affinity. Various compounds obtained from Merrill Dow Pharmaceuticals and the Eli Lilly Company which contained alklaminoethoxy side chains linked to aromatic ring structures had RBA's ranging from 1-0.3. We conclude, as other investigators have also concluded, that the similar binding affinities of various triphenylethylene antiestrogens for TABS and their divergent activities as antiestrogens makes it unlikely that TABS are directly involved in estrogen antagonism. The moderate but significant affinity of TABS for trifluoperazine and other drugs thought to be involved in calmodulin regulation indicates that TABS may be a linked in some way to calmodulin function. The binding of cholesterol and 7-ketocholesterol is also significant and may indicate that TABS are involved in cholesterol metabolism.


Helicobacter pylori IgA and IgG antibodies, serum pepsinogen I and the risk of gastric cancer: changes in the risk with extended follow-up period.
The prediction of Helicobacter pylori antibodies immunoglobulin A (IgA) and immunoglobulin G (IgG) and serum pepsinogen I (PG I) on gastric cancer occurrence was studied in a nested case-control study, based on 225 incident cancer cases and 435 matched controls from a Finnish cohort followed from 1966-1991. The odds ratio of noncardia gastric cancer between infected and noninfected persons was 3.12 (95% confidence interval (CI)=1.97-4.95) for elevated IgA and 2.88 (CI: 1.63-5.07) for elevated IgG antibodies. The odds ratio between low and high PG I was 2.24 (CI: 1.43-3.49). The strength of association was significant for IgA antibodies during the total follow-up, but for IgG antibodies this was only true for follow-up periods of 15 years or more. IgA antibodies were significantly associated with all registered histological subtypes apart from intestinal type adenocarcinoma. The highest gastric cancer risk was found among individuals with simultaneously elevated IgA and IgG antibodies and low PG I with an odds ratio of 10.9 (CI: 4.31-27.7) in comparison with those who were negative for both antibodies and had normal PG I. Elevated IgA and IgG antibodies and low PG I were not associated with cancers of the gastric cardia. The findings support the hypothesis that H. pylori infection is a cause of noncardia gastric cancer. Although elevated H. pylori IgA and IgG antibodies and low PG I independently could predict the occurrence of noncardia gastric cancer, their power to do so varied with the stage and length of the follow-up period and it increased when they were applied in combination.


Expression of diverse and functional TCR gamma and Ig heavy chain transcripts in fetal liver cells cultured with interleukin-7.
We have previously shown that specific T cell receptor (TCR) gamma V regions genes (V gamma 4 and V gamma 6) are rearranged and expressed by murine fetal liver (FL) cells cultured with IL-7. The present studies determined that the sequences of the TCR V region gene transcripts expressed in response to IL-7 included diverse and functional sequences expressed by thymocyte and peripheral V gamma 4+ and V gamma 6+ T cells, indicating that the IL-7-induced expression of these genes is functionally relevant and mimics normal in vivo developmental events of gamma delta T cells. We found that more than 50% of these TCR transcripts had N region diversity. The presence of N region diversity indicates that these TCR rearrangements took place in vitro, presumably in response to IL-7, because fresh (uncultured) FL cells do not produce detectable terminal deoxynucleotidyl transferase (TdT) mRNA or protein. We also found that 100% of immunoglobulin (Ig) VH7183-JH4 transcripts from FL cells cultured with IL-7 had N region diversity at the V-DJ region, while only 40% of Ig VH7183-JH4 transcripts from FL cells cultured in the absence of IL-7 had N region diversity at this region. FL cell cultures supplemented for 7 days with IL-7 had increased TdT mRNA and protein levels. However, since 1-day culture of FL cells with or without IL-7 resulted in induction of expression of TdT, IL-7 probably does not directly stimulate TdT expression, but increases the development and expansion of TdT+ lymphoid cells. These findings implicate IL-7 as a regulator of the molecular signals involved in controlling TCR gamma rearrangement and diversity, and provide an in vitro system for studying the regulation of TdT and N region diversity in B and T lymphoid progenitors by environmental signals.


A comparative study on the measurement properties of Dermatology Life Quality Index (DLQI), DLQI-Relevant and Skindex-16.
Dermatology Life Quality Index (DLQI) and Skindex-16 are among the most commonly used dermatology-specific health-related quality-of-life (HRQoL) instruments. DLQI has two common scoring methods, the original and the DLQI-Relevant (DLQI-R) modification. Head-to-head comparisons of the measurement properties of the DLQI, DLQI-R and Skindex-16 are currently lacking. We aim to compare the measurement properties of the DLQI, DLQI-R and Skindex-16. We analysed data from 618 patients with self-reported physician-diagnosed dermatological conditions from a cross-sectional survey carried out in Hungary in early 2020. DLQI, DLQI-R and Skindex-16 were compared in terms of ceiling and floor effects, informativity, convergent validity and known-group validity. Mean DLQI, DLQI-R and Skindex-16 total scores were 3·76 ± 5·03, 4·11 ± 5·34 and 29·36 ± 26·62, respectively. Among patients with a DLQI/DLQI-R total score of zero, 64% reported problems on Skindex-16. Overall, 23-38% of patients with 'not relevant' responses on DLQI items 3 (shopping/home/gardening), 7 (working/studying), 8 (interpersonal problems) and 9 (sexual difficulties) reported problems on their corresponding Skindex-16 items. Average relative informativity (Shannon's evenness index) was the highest for Skindex-16 (0·85), followed by DLQI-R (0·66) and DLQI (0·54). DLQI, DLQI-R and Skindex-16 demonstrated similar convergent validity. DLQI was able to better discriminate between known groups of patients based on overall skin-related HRQoL impairment, whereas DLQI-R and Skindex-16 performed better with respect to self-perceived health status. Skindex-16 seems to be more sensitive than DLQI/DLQI-R in capturing mild impairment in HRQoL. Our findings help to provide a fuller understanding of the difference between DLQI, DLQI-R and Skindex-16 and support the informed choice of instrument for clinical and research purposes.


Excretory/secretory products from in vitro-cultured Echinococcus granulosus protoscoleces.
Cystic hydatid disease (CHD) is caused by infection with Echinococcus granulosus metacestodes and affects humans and livestock. Proteins secreted or excreted by protoscoleces, pre-adult worms found in the metacestode, are thought to play fundamental roles in the host-parasite relationship. In this work, we performed an LC-MS/MS proteomic analysis of the excretory-secretory products obtained from the first 48 h of an in vitro culture of the protoscoleces. We identified 32 proteins, including 18 that were never detected previously in metacestode proteomic studies. Among the novel identified excretory-secretory products are antigenic proteins, such as EG19 and P-29 and a calpain protease. We also identified other important protoscolex excretory-secretory products, such as thioredoxin peroxidase and 14-3-3 proteins, which are potentially involved in evasion mechanisms adopted by parasites to establish infection. Several intracellular proteins were found in the excretory-secretory products, revealing a set of identified proteins not previously thought to be exposed at the host-parasite interface. Additionally, immunological analyses established the antigenic profiles of the newly identified excretory-secretory products and revealed, for the first time, the in vitro secretion of the B antigen by protoscoleces. Considering that the excretory-secretory products obtained in vitro might reflect the products released and exposed to the host in vivo, our results provide valuable information on parasite survival strategies in adverse host environments and on the molecular mechanisms underpinning CHD immunopathology.


Predicting delayed methotrexate elimination in pediatric acute lymphoblastic leukemia patients: an innovative web-based machine learning tool developed through a multicenter, retrospective analysis.
High-dose methotrexate (HD-MTX) is a potent chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). HD-MTX is known for cause delayed elimination and drug-related adverse events. Therefore, close monitoring of delayed MTX elimination in ALL patients is essential. This study aimed to identify the risk factors associated with delayed MTX elimination and to develop a predictive tool for its occurrence. Patients who received MTX chemotherapy during hospitalization were selected for inclusion in our study. Univariate and least absolute shrinkage and selection operator (LASSO) methods were used to screen for relevant features. Then four machine learning (ML) algorithms were used to construct prediction model in different sampling method. Furthermore, the performance of the model was evaluated using several indicators. Finally, the optimal model was deployed on a web page to create a visual prediction tool. The study included 329 patients with delayed MTX elimination and 1400 patients without delayed MTX elimination who met the inclusion criteria. Univariate and LASSO regression analysis identified eleven predictors, including age, weight, creatinine, uric acid, total bilirubin, albumin, white blood cell count, hemoglobin, prothrombin time, immunological classification, and co-medication with omeprazole. The XGBoost algorithm with SMOTE exhibited AUROC of 0.897, AUPR of 0.729, sensitivity of 0.808, specificity of 0.847, outperforming the other models. And had AUROC of 0.788 in external validation. The XGBoost algorithm provides superior performance in predicting the delayed elimination of MTX. We have created a prediction tool to assist medical professionals in predicting MTX metabolic delay.


Exenatide Reduces Tumor Necrosis Factor-α-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction.
Tumor necrosis factor-α (TNF-α) plays an important role in progressive contractile dysfunction in several cardiac diseases. The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species (ROS)- and mitochondria-dependent apoptosis. Glucagon-like peptide-1 (GLP-1) or its analogue exhibits protective effects on the cardiovascular system. The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-α-treated cardiomyocytes in vitro. Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention; TNF-α group, with cells incubated with TNF-α (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide; and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-α (40 ng/ml) stimulation. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups. Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h. Also, exenatide inhibited excessive ROS production and maintained MMP. Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures. These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis; the anti-apoptotic effects may be associated with protection of mitochondrial function.


Application of cement-augmented pedicle screws in elderly patients with spinal tuberculosis and severe osteoporosis: a preliminary study.
Surgical management of elderly patients with spinal tuberculosis and severe osteoporosis is challenging. Cement-augmented pedicle screws (CAPS) have been specifically designed for elderly patients with osteoporotic spines. Herein, we investigated the feasibility of CAPS applied in elderly patients with spinal tuberculosis and severe osteoporosis. We retrospectively analyzed data of patients with spinal tuberculosis and severe osteoporosis between January 2017 and January 2021. Surgical data, including surgical duration and intraoperative blood loss, were recorded. Radiological parameters, such as correction of regional kyphotic angle and screw loosening, were also evaluated. Additionally, visual analog scores (VAS) and Oswestry disability index (ODI) were used to evaluate back pain and functional recovery, respectively. Erythrocyte sedimentation (ESR) and C-reactive protein (CRP) concentrations were detected to assess tuberculosis activity. The presence of complications and fusion rate was also assessed. A total of 15 patients were included in this study. The surgical duration was 263.0 ± 56.2 min, with an average blood loss of 378.7 ± 237.0 ml. The correction of regional kyphotic angle was 12.4° ± 15.0°, and it was well maintained until the final follow-up. The mean VAS decreased from 6.0 ± 1.2 points to 0.5 ± 0.6 points, and ODI reduced from 37.8% ± 7.6% to 8.3% ± 2.8% (P < 0.01). At the final follow-up, ESR and CRP levels were within normal range. Bony fusion occurred in all patients, with an average fusion duration of 8.8 ± 1.5 months. No cases of pedicle screw pullout, screw loosening, or pseudoarthrosis occurred. Tuberculosis recurrence and dissemination were not observed during the follow-ups. CAPS fixation is an effective and safe technique to achieve solid fixation and favorable clinical outcomes in elderly patients with spinal tuberculosis and severe osteoporosis.


Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress.
Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial-mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.


Electrical discharge machining of ceramic nanocomposites: sublimation phenomena and adaptive control.
The productivity of electrical discharge machining (EDM) is relatively low owing to the natural laws of electrical erosion. Precise EDM demands uninterrupted control of the discharge gap and adjustment of process parameters. It is particularly critical for processing large workpieces with complex linear surfaces and for materials with threshold conductivities such as the new advanced ceramic nanocomposites Al2O3+TiC and Al2O3+SiCw+TiC(30-40%). In these cases, adequate flushing of erosion products is hampered by the geometry of the working space or by the small value of the required discharge gap, which does not exceed 2.2-2.5 μm. The methods of adaptive control in modern computer numerical control systems of EDM equipment based on measuring the electrical parameters in the working zone have been shown to be ineffective in the cases described above. This study aims to investigate the natural phenomena of material sublimation under discharge pulses for conductive ceramics and nanocomposites. The measured conductivities of the samples are higher than the percolation threshold. However, the question of machinability remains open owing to detected processing interruptions and poor quality of machined surfaces. New knowledge on EDM of conductive ceramics and nanocomposites can improve the final quality of the machined surfaces and productivity of the method by the introduction of advanced monitoring and control methods based on acoustic emissions. The manuscript presents an up-to-date overview and current state of the research on the subject area. The obtained morphology of the samples and discussion of the findings complete the experimental part of the study. The scientific basis for a new type of adaptive control system is provided. This can improve the effectiveness of parameter control for machining conductive ceramics and nanocomposites and contribute to an increase in the EDM performance for the most critical cases.


Trabecular bone mineral density correlations using QCT: Central and peripheral human skeleton.
Musculoskeletal injuries to the lower leg and foot-ankle joint are associated with external mechanical loads resulting from motor vehicle crashes, under body blasts, falls from height, or sports. As an intrinsic material property, the bone mineral density (BMD) is related to bone strength. The clinically recognized biological sites for BMD evaluation are the hip and spine. The focus of this study was to define the correlation between BMD from standard clinical sites (hip and lumbar spine) compared to BMD from non-standard sites (foot-ankle-distal tibia bones). Twenty-one post-mortem human subjects (PMHS) with mean age, height, and mass of 63 ± 11 years, 179 ± 7 cm, and 86 ± 13 kg, respectively were used for analysis. Clinical BMD software (Mindways Software, Inc.) was used for trabecular BMD quantification using quantitative computed tomography (QCT). In quantification of BMD of the foot-ankle-distal tibia (hind foot), the trabecular BMD of the talus (316 ± 86mg/cc) was highest followed by the distal tibia (238 ± 72 mg/cc) and then calcaneus (147 ± 51 mg/cc). To correlate BMD values from foot bone regions with the central skeleton BMD values within the same PMHS, there were 18 lumbar spine and 12 hip BMDs available. The BMD of the distal tibia correlated best with the hip intertrochanter BMD (R2 of 0.72). Calcaneus BMD best correlated with the hip femoral neck BMD (R2 = 0.64). In summary, the hind foot bone BMD values correlated better with the hip as compared to the lumbar spine BMD from the same PMHS. These findings indicate that, in the absence of a direct measure of foot-bone BMD, hip BMD might be a better predictor of injury risk to hind foot rather than lumbar spine BMD, or alternatively, calcaneal trabecular BMD can be used to predict the risk of injury to hip. Further, these relationships between central and peripheral regions can also be implemented in finite element models for improved failure predictions.


Mobius Assembly.
Mobius Assembly is a versatile and user-friendly DNA Assembly method, which facilitates rapid and simple generation of DNA constructs. Mobius Assembly combines high cloning capacity and vector toolkit simplicity to streamline combinatorial assemblies. It is a two-level hierarchical modular cloning system that enables quadruple assembly augmentation. It adopts the 4 bp standard overhangs defined by Phytobricks to promote standard part sharing, and it can be made compatible with different chassis. Furthermore, Mobius Assembly reduces domestication requirements and uses chromogenic proteins to facilitate the identification of positive assemblies.


Comparative quantitative evaluation of hepatic clearance of diethyl-IDA and para-butyl-IDA in jaundiced and non-jaundiced patients.
A method for comparative measurement of hepatic clearance of different hepatobiliary agents is described and the clinical use of diethyl-IDA and parabutyl-IDA is discussed. The study was performed with both radiopharmaceuticals in 13 patients with hepatobiliary disease with serum bilirubin ranging from 0.3 to 16.4 mg/100 ml. Diethyl-IDA is preferable for a qualitative evaluation of hepatobiliary disease because of its higher hepatic clearance and faster biliary excretion rate. Parabutyl-IDA is superior for measuring the hepatocytic uptake function, due to the low urinary excretion and the absence of an apparent re-entry from liver to plasma, even in patients with obstructive jaundice. In contrast, an appreciable re-entry can be demonstrated for diethyl-IDA.


The ras-related ral gene maps to chromosome 7p15-22.
Human cDNAs coding for the new protein ral that shares 50% homology with the ras proteins have been recently isolated. A 600-bp fragment carrying mainly the coding region was used to localize the ral gene by hybridization with sorted chromosomes and in situ hybridization. Direct molecular hybridization on sorted chromosomes using a single laser illumination allowed the assignment of the ral gene to a region of the flow karyotype containing chromosomes 7, 8 and X. With dual laser analysis ral was assigned to the fraction containing chromosome 7. In the 331 human metaphases hybridized with the 3H-labelled insert, the silver grain distribution showed a unique major signal on chromosome 7p15-22.


Cctionic selectivity of bimolecular membranes in the presence of nystatin and amphotericin B.
Ergosterin or 7-dehydrocholesterin-containing artificial membranes are selectively permeable for cations of alkaline metals in aqueous solutions of nistatin and amphotericine B. Membrane permeability changes spontaneously within several tens of minutes from the cation to the anion one. A decrease of temperature, an increase of medium pH or introduction of dimethylsulphoxide into aqueous solution inhibit, while the addition of calcium accelerate this transition.


Polydopamine coating of living diatom microalgae.
Many microorganisms produce specific structures, known as spores or cysts, to increase their resistance to adverse environmental conditions. Scientists have started to produce biomimetic materials inspired by these natural membranes, especially for industrial and biomedical applications. Here, we present biological data on the biocompatibility of a polydopamine-based artificial coating for diatom cells. In this work, living Thalassiosira weissflogii diatom cells are coated on their surface with a polydopamine layer mimicking mussel adhesive protein. Polydopamine does not affect diatoms growth kinetics, it enhances their resistance to degradation by treatment with detergents and acids, and it decreases the uptake of model staining emitters. These outcomes pave the way for the use of living diatom cells bearing polymer coatings for sensors based on living cells, resistant to artificial microenvironments, or acting as living devices for cells interface study.


Determination of a functional ancestral sequence and definition of the 5' end of A-type mouse L1 elements.
The complete nucleotide sequence of L1Md-A13, a 6372 base-pair (bp) member of the L1Md repetitive family isolated from a BALB/c mouse genomic DNA library, is reported. The nucleotide sequence of 4331 bp from the 5' end of L1Md-9, which is located in the beta-globin complex of the C57BL/10 mouse, is also reported. Parsimony analysis of these sequences plus two previously reported L1Md sequences allows the determination of an ancestral L1Md sequence. Analysis of the L1Md population indicates that this ancestral sequence is likely to represent a functional L1 sequence. This ancestral sequence confirms that the length (1137 bp and 3900 bp) and relationship (14 bp overlap) of the two large open reading frames previously reported are conserved features of the L1Md family. It also allows the determination of an ancestral amino acid sequence for these two open reading frames. Full-length L1Md elements have one of two sequences tandemly repeated at the 5' end. These two monomers are called A-type and F-type. Our data define the 5' end of A-type full-length L1Md elements. L1Md elements of the A-type have varying numbers of tandemly repeated 208 bp monomers, but each element ends about 78 bp from the 5' end of the terminal 208 bp monomer.


Enzyme immunometric assay for the determination of pregnancy associated plasma protein A (PAPP-A) with the antigen as solid phase (conjoint IEMA).
Purified pregnancy associated plasma protein A (PAPP-A) can be effectively bound to polystyrene microtitre plates. This immobilized antigen competes with the added serum PAPP-A of unknown concentration for the limited amount of peroxidase-labeled monospecific anti-PAPP-A antibody incubated simultaneously. The sensitivity is 0.1 WHO unit/ml and non-specific binding is 1.0%.


Evaluation of iron chelating and antioxidant potential of Epilobium hirsutum for the management of iron overload disease.
The present study deals with the investigation of iron chelating and antioxidant potential of Epilobium hirsutum in iron-overloaded rats. Iron overload was induced by 6 IP injections of Iron dextran (12.5mg/100g) administered uniformly over a period of 30 days. Different fractions of E. hirsutum were given orally and deferoxamine (DFO) subcutaneously for 30 days. The extent of iron chelation and various biochemical parameters were estimated on 15th and 30th day of treatment. In-vitro study was assessed by EDTA and DFO method; the results exhibited a dose-dependant iron chelation. The methanolic fraction of methanolic extract (MFME) and methanolic fraction of aqueous extract (MFAE) of E. hirsutum showed significant (p<0.01) iron chelating and antioxidant potential as compared to disease control (DC) rats. The animals treated with MFME and MFAE of E. hirsutum showed significant (p<0.01) vital organ protection as compared to DC rats. The animals treated for longer duration (30th day) reveals better iron chelation potential than shorter ones (15th day). Superior iron chelation was seen at higher dose (300mg/kg) as compared to lower dose (150mg/kg). Taken into an account, our result reveals the reversible iron chelating and antioxidant ability of E. hirsutum and gives some evidence for its possible mechanism via excretion of iron in urine and feces.


Rapid differentiation among bacteria that cause gastroenteritis by use of low-resolution Raman spectroscopy and PLS discriminant analysis.
Use of classical microbiological methods to differentiate bacteria that cause gastroenteritis is cumbersome but usually very efficient. The high cost of reagents and the time required for such identifications, approximately four days, could have serious consequences, however, mainly when the patients are children, the elderly, or adults with low resistance. The search for new methods enabling rapid and reagentless differentiation of these microorganisms is, therefore, extremely relevant. In this work the main microorganisms responsible for gastroenteritis, Escherichia coli, Salmonella choleraesuis, and Shigella flexneri, were studied. For each microorganism sixty different dispersions were prepared in physiological solution. The Raman spectra of these dispersions were recorded using a diode laser operating in the near infrared region. Partial least-squares (PLS) discriminant analysis was used to differentiate among the bacteria by use of their respective Raman spectra. This approach enabled correct classification of 100% of the bacteria evaluated and unknown samples from the clinical environment, in less time ( approximately 10 h), by use of a low-cost, portable Raman spectrometer, which can be easily used in intensive care units and clinical environments.


Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.
Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.


Outcomes of patients undergoing lung resection for drug-resistant TB and the prognostic significance of pre-operative positron emission tomography/computed tomography (PET/CT) in predicting treatment failure.
Surgery remains an adjunctive treatment for drug-resistant tuberculosis (DR-TB) treatment failure despite the use of bedaquiline. However, there are few data about the role of surgery when combined with newer drugs. There are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT remains unknown. We performed a prospective observational study of 57 DR-TB patients referred for surgery at Groote Schuur Hospital between 2010 and 2016. PET-CT was performed if there was nodal disease or disease outside the area of planned resection but did not influence treatment decisions. 24-month treatment success post-surgery (cure or treatment completion), including all-cause mortality, was determined. 35/57 (61.4%) patients (median age 40 years; 26% HIV-infected) underwent surgery and 22/57 (38.6%) did not (11 patients were deemed unsuitable due to bilateral cavitary disease and 11 patients declined surgery). Treatment failure was significantly lower in those who underwent surgery compared to those eligible but declined surgery [15/35 (43%) versus 11/11 (100%); relative risk 0.57 (0.42-0.76); p < 0.01). In patients treated with surgery, a post-operative regimen containing bedaquiline was associated with a lower odds of treatment failure [OR (95%CI) 0.06 (0.00-0.48); p = 0.007]. Pre-operative PET-CT (n = 25) did not predict treatment outcome. Resectional surgery for DR-TB combined with chemotherapy was associated with significantly better outcomes than chemotherapy alone. A post-operative bedaquiline-containing regimen was associated with improved outcome; however, this finding may have been confounded by higher use of bedaquiline and less loss to follow-up in the surgical group. However, PET-CT had no prognostic value. These data inform clinical practice in TB-endemic settings. This work was supported by the South African MRC (RFA-EMU-02-2017) and the EDCTP (TMA-2015SF-1043 & TMA- 1051-TESAII).


Ovarian aging and bone metabolism in menstruating women aged 35-50 years.
The aim of this study was to investigate the relationships between the levels of gonadotrophins, estradiol, inhibin-b and bone mass and turn-over in regularly menstruating women aged 35-50 years. The study group included 87 healthy volunteers from the community aged 35-50 years. Bone mineral density of lumbar vertebras, wards triangle, throchanter, femur neck, bone resorption and formation markers were studied as well as the serum levels of gonadotrophins, estradiol and inhibin-b on the day 3 of menstrual cycle. The gonadotrophin levels showed significant positive relation with age, whereas inhibin-b and estradiol levels showed significant negative correlation with age. The gonadotrophins and estradiol levels had no significant association with bone mass and bone formation markers. Increased gonadotrophin (p < 0.001) levels and decreased inhibin-b (p < 0.01) levels independent from age were correlated with increased bone resorption. Gonadotrophins, estradiol, age, inhibin-b, body mass index (BMI) were the confounding factors for bone resorption (p = 0.015, R(2) = 0.190) and lumbar bone mass (p = 0.041, R(2) = 0.148). Multivariate analysis showed an independent contribution of inhibin-b and BMI in the prediction of lumbar bone mass. This findings suggested that estradiol was not the only factor responsible for bone loss and decrease in reproductive function because increased gonadotrophins and decreased inhibin-b levels might trigger some changes in bone metabolism prior to the menopause.


Neuroprotective effects of resident microglia following acute brain injury.
Microglia quickly react to various neurodegenerative processes by producing cytokines and eliminating cellular debris via phagocytosis. These events are also associated with an increased proliferation of microglia, which derive from resident progenitors and those present in the bone marrow. However, it is not clear whether the innate immune response by resident or newly differentiated microglia is beneficial or detrimental to the central nervous system. The aim of this study was to determine the impact of an altered immune response following acute excitotoxicity. Sodium nitroprusside (SNP) or kainic acid (KA) was administered in the brain of various groups of mice, and the extent of neurodegeneration, myelin damage, and inflammation was evaluated within a period of 2 weeks. We used synthetic glucocorticoid (GC), myeloid differentiation factor 88 (MyD88)-deficient mice to suppress nuclear factor kappaB (NF-kappaB) signaling and transgenic mice that express the thymidine kinase (TK) protein under the control of the CD11b promoter to determine the role of proliferating and infiltrating microglia in acute models of brain injury. Neurodegeneration was more extensive in GC-treated and MyD88-deficient mice, suggesting that NF-kappaB signaling and microglia activation are potent neuroprotective mechanisms in the presence of SNP. KA was also highly toxic to neurons of the amygdala in MyD88 knockout mice but not in their WT littermates. Although bone marrow-derived cells are clearly attracted to neurodegenerative areas, preventing their infiltration and differentiation did not affect the extent of SNP-related damage. These data indicate that MyD88/NF-kappaB signaling in resident non-proliferating microglia plays a critical role by restricting damage during acute excitotoxicity.


Change in volumetric tumor growth rate after cytotoxic therapy is predictive of overall survival in recurrent glioblastoma.
Alterations in tumor growth rate (TGR) in recurrent glioblastoma (rGBM) after treatment may be useful for identifying therapeutic activity. The aim of this study was to assess the impact of volumetric TGR alterations on overall survival (OS) in rGBM treated with chemotherapy with or without radiation therapy (RT). Sixty-one rGBM patients treated with chemotherapy with or without concomitant radiation therapy (RT) at 1st or 2nd recurrence were retrospectively examined. Pre- and post-treatment contrast enhancing volumes were computed. Patients were considered "responders" if they reached progression-free survival at 6 months (PFS6) and showed a decrease in TGR after treatment and "non-responders" if they didn't reach PFS6 or if TGR increased. Stratification by PFS6 and based on TGR resulted in significant differences in OS both for all patients and for patients without RT (P < 0.05). A decrease of TGR (P = 0.009), smaller baseline tumor volume (P = 0.02), O6-methylguanine-DNA methyltransferase promoter methylation (P = 0.048) and fewer number of recurrences (P = 0.048) were significantly associated with longer OS after controlling for age, sex and concomitant RT. A decrease in TGR in patients with PFS6, along with smaller baseline tumor volume, were associated with a significantly longer OS in rGBM treated with chemotherapy with or without radiation. Importantly, all patients that exhibited PFS6 also showed a measurable decrease in TGR.


CXCL5 promotes tumorigenesis and angiogenesis of glioblastoma via JAK-STAT/NF-κb signaling pathways.
The tumor microenvironment contains chemokines that play a crucial role in various processes, such as tumorigenesis, inflammation, and therapy resistance, in different types of cancer. CXCL5 is a significant chemokine that has been shown to promote tumor proliferation, invasion, angiogenesis, and therapy resistance when overexpressed in various types of cancer. This research aims to investigate the impact of CXCL5 on the biological functions of glioblastoma (GBM). The TCGA GBM and GEO databases were utilized to perform transcriptome microarray analysis and oncogenic signaling pathway analysis of CXCL5 in GBM. Validation of CXCL5 expression was performed using RT-qPCR and Western Blot. The impact of CXCL5 on cell proliferation, tumorigenesis, and angiogenesis in GBM was assessed through various methods, including cell proliferation assay, cloning assay, intracranial xenograft tumor models, and tube formation assay. Clinical prognosis was evaluated in 59 samples of gliomas with varying degrees of malignancy (grades 2, 3, and 4) and the TCGA GBM database, based on CXCL5 expression levels. The activities of the JAK-STAT and NF-κB signaling pathways were detected using Western Blot. The expression of CXCL5 was highly enriched in GBM. Moreover, the inhibition of CXCL5 showed a significant efficacy in suppressing cellular proliferation and angiogenesis, resulting in extended survival rates in xenograft mouse models in comparison to the control group. Notably, pretreatment with dapsone exhibited a reversal of the impact of CXCL5 on the formation of colonies and tubes in GBM cells. Elevated expression of CXCL5 was correlated with poor outcomes in GBM patients. Furthermore, the overexpression of CXCL5 has been associated with the activation of JAK-STAT and NF-κB signaling pathways. CXCL5 plays an important role in tumorigenesis and angiogenesis, indicating the potential for novel therapies targeting CXCL5 in GBM.


Predictive value of clinical factors for successful endoscopic correction of primary vesicoureteral reflux grades III-IV.
To evaluate the clinical factors that influence the outcome of endoscopically treated primary grade III and IV vesicoureteral reflux (VUR). Excluding secondary VUR and patients with incomplete follow up, a retrospective and prospective cohort observational study was performed on 90 children (130 renal units) with primary grade III or IV reflux treated endoscopically with Polytef or Macroplastique from March 1997 to January 2004. All patients underwent voiding cystourethrography (or galactose-based sonocystourethrography), dimercaptosuccinic acid (DMSA) scan, renal ultrasound and clinical exploration of micturition. Data were collected on age, gender, urinary tract infection (UTI), bilaterality, renal scarring, voiding dysfunction, and success rate. A new factor was defined, ureteral dilatation of the renal unit (not related to grade according to findings of pelvi-calyceal images), and graded by a single pediatric urologist blinded to its International Classification grade. The male-to-female ratio of patients was 2.91. Reflux was bilateral in 44.4%. There was UTI at presentation in 64 cases, and 21 newborns had been prenatally diagnosed (ratio M/F 5.2:1). We found a strong relation between the incidence of renal scarring at presentation and voiding dysfunction (P<0.01). Cure rate at first injection was 64%. While univariate analysis appeared to show a strong association between resolution at first injection and bilaterality, voiding dysfunction, nephropathy and ureteral dilatation grade, with simultaneous logistic regression, the only statistically significant predictor was the presence of high-grade dilatation vs low ureteral dilatation (P<0.001; OR 0.045; 95% CI 0.01-0.16). Progression of renal damage was noted especially in patients with voiding dysfunction (P=0.053), bilaterality (P=0.034), and severe ureteral dilatation (P<0.001). The relationship between success rate of endoscopic treatment and grade of ureteral dilatation is demonstrated. Other factors significantly involved in the resolution of VUR are voiding dysfunctional syndrome, bilateralism of reflux, and scarring on initial DMSA. Gender, age, number of infections during follow up and prenatal diagnosis do not influence the outcome of endoscopic treatment.


Hallmarks of immune response in COVID-19: Exploring dysregulation and exhaustion.
One and half year following the occurrence of COVID-19 pandemic, significant efforts from laboratories all over the world generated a huge amount of data describing the prototypical features of immunity in the course of SARS-CoV-2 infection. In this Review, we rationalize and organize the main observations, trying to define a "core" signature of immunity in COVID-19. We identified six hallmarks describing the main alterations occurring in the early infection phase and in the course of the disease, which predispose to severe illness. The six hallmarks are dysregulated type I IFN activity, hyperinflammation, lymphopenia, lymphocyte impairment, dysregulated myeloid response, and heterogeneous adaptive immunity to SARS-CoV-2. Dysregulation and exhaustion came out as the trait d'union, connecting abnormalities affecting both innate and adaptive immunity, humoral and cellular responses.


Reactivity of OH and CH3OH Between 22 and 64 K: Modelling the Gas Phase Production of CH3O in Barnard 1B.
In the last years, ultra-low temperature chemical kinetic experiments have demonstrated that some gas-phase reactions are much faster than previously thought. One example is the reaction between OH and CH3OH, which has been recently found to be accelerated at low temperatures yielding CH3O as main product. This finding opened the question of whether the CH3O observed in the dense core Barnard 1b could be formed by the gas-phase reaction of CH3OH and OH. Several chemical models including this reaction and grain-surface processes have been developed to explain the observed abundance of CH3O with little success. Here we report for the first time rate coefficients for the gas-phase reaction of OH and CH3OH down to a temperature of 22 K, very close to those in cold interstellar clouds. Two independent experimental set-ups based on the supersonic gas expansion technique coupled to the pulsed laser photolysis-laser induced fluorescence technique were used to determine rate coefficients in the temperature range 22-64 K. The temperature dependence obtained in this work can be expressed as k(22-64 K) = (3.6 ± 0.1) × 10-12(T/300 K)-(1.0±0.2) cm3 molecule-1 s-1. Implementing this expression in a chemical model of a cold dense cloud results in CH3O/CH3OH abundance ratios similar or slightly lower than the value of ∼ 3 × 10-3 observed in Barnard 1b. This finding confirms that the gas-phase reaction between OH and CH3OH is an important contributor to the formation of interstellar CH3O. The role of grain-surface processes in the formation of CH3O, although it cannot be fully neglected, remains controversial.


Behaviour and time-course of sleep disordered breathing in patients with acute coronary syndromes.
To our knowledge, no study has examined the persistence of sleep disordered breathing in acute coronary syndrome (ACS) patients. We examined the time course of SDB in ACS patients by assessing them within days of the acute event and again after 6 months. Consecutive patients with ACS were asked to voluntarily participate in the study. Patients underwent an overnight polysomnography (PSG) approximately 3 days after the acute event. Patients with an apnea hypopnea index (AHI) > 10/h then underwent another PSG after they were stable (approximately 6 months). Fifty patients were studied. First PSG showed an AHI was 23.1 +/- 3.6/h. A second PSG was performed 6.1 +/- 0.3 months later on 21 patients and showed an AHI > 10/h in the first assessment. The AHI and the obstructive apnea index did not change over the 6 months. However, the central apnea index all was lower at the second assessment.


[Psycho-social and economic reintegration of women operated for urogenital fistula].
To study the psycho-social and economic reintegration of women operated for genital fistula in Congo. This was a descriptive observational study conducted in Brazzaville and Ewo, Republic of Congo, from April 1 to October 31, 2018. It included patients operated for genital fistula between 2008 and 2017. Variables of interest were socio-demographic, reproductive and clinical characteristics. The analysis was performed using the SPSS 20 software. The overall, 34 patients were studied, with age ranging from 29 to 65 years old with a median of 43 (39, 50) year. The context of fistula occurrence was obstetrical in 24 women (70%). The Practice of an income-generating activity before, during and after fistula was 76%; 32% and 64% (P=0.0007). Concerning the psychological status, in these women, self-esteem went from 26% to 73% (P=0.0003) and the prevalence of suicidal thoughts went from 29% before fistula treatment to 0% after (P=0.0009). The tendency to isolate themselves went from 44% before fistula cure to 3% after (P=0.00008). With regards to reproductive life, 54% of women had no desire for maternity and 17% did not have a desire of sexual intercourse. Only 26% of women benefited from the psychologist. Support. In this series, we observed a resumption of income-generating activities in women operated for a treatment of urogenital fistula and a psychological recovery with an increase in self-esteem and a decrease in suicidal thoughts. 4.


Head mounted telemetry system for seizures monitoring and sleep scoring on non-human primate.
Radio telemetry systems are a useful way to continuously monitor broad electrical neuronal activity in behaving animals. It can also be used to study sleep disturbances or monitor seizure activity. Many different telemeter styles are available, but the more versatile and cost-efficient ones are the head mounted systems. They permit long-term recordings and allow more flexibility in the recordings. However, there are currently no such system available for non-human primate (NHP). In fact, the choices for NHP telemetry solutions are very limited. Here, we present a chronically implantable 3D printed chamber specifically designed to accommodate a rodent head-mounted system (RodentPACK) onto a NHP's head. We recorded EEG signal for more than a year, confirmed quality of the signal, and the ability to use the data to monitor sleep activity. We also used two of our epileptic animals to validate the embedded alarm system for real time seizure monitoring. While initially not designed for NHP, but with a minimum number of adaptions, this telemeter is in fact perfectly suitable for NHP experiments. Since early medical intervention during seizures is critical to avoid status epilepticus and to save the animal's life, real time seizures monitoring is becoming a safety requirement in many NHP studies. This method refines the current seizure monitoring methods for NHP and creates a flexible telemetry solution.


Urinary ascites: complication of umbilical artery catheterization.
In the newborn, intraperitoneal extravasation of urine from a urachal laceration may follow an attempt at umbilical artery catheterization. Clinical results of this injury are neonatal ascites, anuria, and azotemia. Herein, we describe a case of iatrogenic bladder injury with successful management following late detection. The anatomy of the urachus and bladder in the newborn are reviewed as well as clues to the diagnosis of neonatal urinary ascites.


Degradation of volatile organic compounds with thermally activated persulfate oxidation.
This study investigated the extent and treatability of the degradation of 59 volatile organic compounds (VOCs) listed in the EPA SW-846 Method 8260B with thermally activated persulfate oxidation. Data on the degradation of the 59 VOCs (in mixture) reacted with sodium persulfate in concentrations of 1 g l(-1) and 5 g l(-1) and at temperatures of 20 degrees C, 30 degrees C, and 40 degrees C were obtained. The results indicate that persulfate oxidation mechanisms are effective in degrading many VOCs including chlorinated ethenes (CEs), BTEXs and trichloroethanes that are frequently detected in the subsurface at contaminated sites. Most of the targeted VOCs were rapidly degraded under the experimental conditions while some showed persistence to the persulfate oxidation. Compounds with "CC" bonds or with benzene rings bonded to reactive functional groups were readily degraded. Saturated hydrocarbons and halogenated alkanes were much more stable and difficult to degrade. For those highly persulfate-degradable VOCs, degradation was well fitted with a pseudo first-order decay model. Activation energies of reactions of CEs and BTEXs with persulfate were determined. The degradation rates increased with increasing reaction temperature and oxidant concentration. Nevertheless, to achieve complete degradation of persulfate-degradable compounds, the systems required sufficient amounts of persulfate to sustain the degradation reaction.


Effects of oral white willow bark (Salix alba) and intravenous flunixin meglumine on prostaglandin E2 in healthy dairy calves.
White willow bark (WWB) is commonly used in combination with other medicinal herbs and analgesics to alleviate inflammatory pain in disbudded calves under organic management, but there is no evidence to confirm an effect of WWB on inflammatory biomarkers in calves. The objective of this study was to determine whether WWB affects the inflammatory biomarker prostaglandin E2 (PGE2) in healthy dairy calves. A randomized crossover trial with 2 periods and 5 treatments was used for this experiment. A 7-d washout period was used to minimize carryover effects. The treatments were (1) 57.6 mg/kg oral WWB (low dose; L-WWB), (2) 115.1 mg/kg oral WWB (medium dose; M-WWB), (3) 230.3 mg/kg oral WWB (high dose; H-WWB), (4) 2.2 mg/kg i.v. flunixin meglumine (FM), or (5) no treatment (NT). Calves (n = 25) were randomly assigned to receive 1 of the 25 treatment sequences. Blood samples were collected at 1, 2, and 4 h after administration to determine PGE2 and salicylic acid plasma concentrations. The WWB had 2,171 μg/g (± 4.3% relative standard error) salicin (0.22%). On average, calves in the FM (721 ± 274 pg/mL) treatment had lower PGE2 than calves in all other treatments. Calves in the NT (2,606 ± 271 pg/mL), L-WWB (2,509 ± 276 pg/mL), M-WWB (2,343 ± 270 pg/mL), and H-WWB (3,039 ± 270 pg/mL) treatments had similar PGE2 averaged across sampling times. Calves in the L-WWB (23.4 ± 1.9 ng/mL), M-WWB (21.5 ± 1.9 ng/mL), and H-WWB (23.3 ± 1.9 ng/mL) treatments had similar maximum salicylic acid plasma concentrations. Results from this study indicate that the WWB doses used in this experiment were ineffective at achieving dose-dependent PGE2 and salicylic acid plasma concentration responses.


User-centered visual explorer of in-process comparison in spatiotemporal space.
We propose a user-centered visual explorer (UcVE) for progressive comparing multiple visualization units in spatiotemporal space. We create unique unit visualization with the customizable aggregated view based on the visual metaphor of flower bursts. Each visualization unit is encoded with the abstraction of spatiotemporal properties. To reduce user cognition load, UcVE allows users to visualize, save, and track in-the-process exploration results. In coordination of storage sequence and block tracking views, UcVE can facilitate comparison with multiple visualization units concurrently, selected from historical and current exploration results. UcVE offers a flexible geo-based layout, with aggregation functions and temporal views of the timeline with categorized events, to maximize the user's exploration capabilities. Finally, we demonstrate the usefulness by using COVID-19 datasets, case studies with different user scenarios, and expert feedback.


Synthesis and biological evaluation of lipophilic iron chelators as protective agents from oxidative stress.
Lipophilic Fe(III) chelators were synthesized and shown to protect oligodendrial cells from oxidative damage induced by Fe(III) and hydrogen peroxide.


[Therapy of non-metastatic Ewing's sarcoma (pelvis excluded). Results obtained in 48 cases combining local therapy (radiation and/or surgical) and adjuvant chemotherapy with vincristine, adriamycin, dactinomycin and cyclophosphamide].
Combined therapy was used on a consecutive series of 48 patients with extrapelvic Ewing's sarcoma at the Rizzoli Orthopaedic Institute. The adjuvant chemotherapy protocol (VCR, ADM, D-ACT, EDX) was identical in all patients whereas local treatment consisted of amputation, resection and radiation treatment or radiation alone. At a mean follow-up of 58 months (39-78) 30 patients (60%) were free of the disease. This is a significantly higher percentage than that obtained in the same period with adjuvant chemotherapy using only 3 drugs (VCR, ADM, EDX). As far as the type of local treatment is concerned, the percentage of local recurrences and metastases was lower when the primary lesion was treated with surgery or surgery combined with radiotherapy, rather than radiation treatment alone. These suggest that if associated with radiation treatment and chemotherapy, surgery can play an important role that should be considered in the treatment of extrapelvic Ewing's sarcoma.


ACTH-induced hyperalgesia in rats.
The injection of ACTH 1--24 into the cerebral ventricles in rats markedly reduces the reaction time in the hot-plate test and the nociception threshold in the tail-stimulation test. Morphine antagonizes and naloxone potentiates this hyperalgesic effect of ACTH. It is proposed that ACTH peptides play a physiological role in nociception.


[Treatment of latent tuberculosis infection].
Latent tuberculosis infection is a key stage in the natural history of tuberculosis, and provides an important period where strategies to prevent the development of disease may be implemented. The treatment of latent tuberculosis infection is well described in many national guidelines. In this review, we attempt to help pneumonologists to implement these guidelines accurately and appropriately, prescribing preventive treatment when the benefit-risk ratio is optimal, providing treatment most safely, performing therapeutic education and incorporating preventive treatment into the full array of measures against tuberculosis.


Peer group interaction of physically abused children.
The aim of this research study was to test the assumption that physically abused children differ significantly from their non-abused peers along dimensions which characterize abusing adults and other social deviants. Nineteen 5-10 year-old physically abused children and 38 non-abused peers were assessed by video-taped behavioral observations during free-flowing social interaction in a playroom. The dimensions tapped were: aggression, warmth, fear, pleasure, concentration, imagination and social participation. The dimension social participation was split into three variables: total social participation, negative participation and positive participation. The data from these nine dimensions was subject to a Pearson's correlation. Given the high correlation amongst these variables the data was subject to a principal components analysis with varimax rotation. From this analysis two components emerged which explained 76.9% of the total variance. These components were designated "social interaction" (component 1) and "hostility" (component 2) and were then subject to analyses of variance. A significant difference was found between the two groups on the "social interaction" component. The implications of these findings were explored and treatment possibilities examined.


Dopamine-loaded poly (butyl cyanoacrylate) nanoparticles reverse behavioral deficits in Parkinson's animal models.
Aim: Parkinson's disease (PD) is a neurological disorder resulting from decreased dopamine (DA) secretion in the brain, which reflects impaired motor function. Thus, a drug-delivery system for releasing DA into the brain would be of crucial importance. Materials & methods: We herein examined the in vivo drug efficiency of novel poly-butyl-cyanoacrylate nanoparticles loaded with DA (DA-PBCA NPs). Results & conclusion: The NPs were able to pass through the blood-brain barrier and improve brain structure and function in the PD animal models. Moreover, we found a reduced α-synucleinopathy in the animal model brains after the NPs administration. Thus, the NPs seem to be a reliable DA delivery system for treating PD patients.


Familial aggregation of endometriosis in the Yale Series.
To investigate the familial aggregation and the risk of endometriosis among the female relatives of women with endometriosis. We also compared the epidemiologic characteristics of women with and without family history of endometriosis. A total of 485 women with endometriosis and 197 infertile women without endometriosis underwent surgical investigation between August 1996 and February 2002. The relative risk of endometriosis in a first-degree relative and the association between potential risk factors was estimated by chi2 and by crude adjusted odds ratios (95% CI). Endometriosis was identified in 9.5% of first-degree relatives of women with endometriosis versus only 1% of controls. The odds ratio for endometriosis in a first-degree relative was 10.21 (95% CI 2.45-42.5; P<0.001). In 3.9% of cases women with endometriosis reported that their mother had been diagnosed with endometriosis and 5.6% of cases that at least one sister had been diagnosed. Compared to the control group the odds ratio for the mother having endometriosis (7.99, 95% CI 1.06-60.1) or at least one sister having (11.55, 95% CI 1.56-85.59) were significantly elevated. Among women with endometriosis who reported a family history of endometriosis, and women with endometriosis who did not report a family history of endometriosis, there were no differences in demographic characteristics, body habitus, or menstrual parameters. Women with endometriosis have a tenfold increased risk of endometriosis in their first-degree relatives.


Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia.
The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension.


Accelerated current-driven multi-objective topology optimization for compact ultrawide-band MIMO antenna design.
In this work, an accelerated current-driven multi-objective topology optimization method is proposed for compact high-isolation ultrawide-band (UWB) multiple input multiple output (MIMO) antenna design. The proposed method takes the current Pareto solutions as the centers to perform fuzzy clustering (FC) and then drives the evolution of individuals in each cluster according to the current distribution characteristics of the clustering centers. Individuals in each cluster purposefully generate antennas with expected performance, thereby accelerating the process of optimization design. The proposed method uses about half the computational cost of traditional algorithms to design a compact (20 × 18 mm2) and high-isolation (>20 dB) UWB MIMO antenna. The proposed method provides a new way for accelerating multi-objective topology optimization with a high design degree of freedom. Also, the optimized antenna is a competitive candidate solution for UWB applications.


Surface morphology of the human ciliary body during prenatal development. A scanning electron microscopic study.
The development of the ciliary body was examined by scanning electron microscopy in human embryos and fetuses with a gestation age of 9.5 to 24 weeks. During this period it was possible to follow up the main morphogenetical events, beginning with the appearance of the first radial folds up to the occurrence of ciliary processes with a rather adultlike arrangement. The ciliary processes observed during week 24 differed from those of the adult eye only by their dimensions and the lack of surface infoldings. A primitive pars plana could only be identified during week 24. The morphological basis for aqueous humor production is discussed.


Correlation of visual analogue scale foot and ankle (VAS-FA) to AOFAS score in malleolar fractures using Indian language questionnare.
Visual analogue scale foot and ankle (VAS-FA score) is a new score, validated in previous studies, but never compared to AOFAS score. Analysis of the two scores using Indian language questionnaire. Fifty patients with Malleolar fractures were assessed for functional outcome, time for calculation of scores, difficulty in correlation and comprehension of the questionnaire, in Malayalam language. The score parameters were compared by SSPSS. There was similarity in pattern of score values in both systems but also a difference between values in each category, with VAS-FA having lower values, reflecting its efficacy. There was significant correlation, similar sensitivity and agreement between the scoring systems. VAS-FA correlated better with patient's outcome and required less time for assessment. This study shows that Indian language VAS-FA has a similar pattern of extracting scores as AOFAS and can be an efficient tool in ankle outcome assessment in Indian patients.


Diagnostic yield and accuracy in a tertiary referral syncope unit validating the ESC guideline on syncope: a prospective cohort study.
To assess in patients with transient loss of consciousness the diagnostic yield, accuracy, and safety of the structured approach as described in the ESC guidelines in a tertiary referral syncope unit. Prospective cohort study including 264 consecutive patients (≥18 years) referred with at least one self-reported episode of transient loss of consciousness and presenting to the syncope unit between October 2012 and February 2015. The study consisted of three phases: history taking (Phase 1), autonomic function tests (AFTs) (Phase 2), and after 1.5-year follow-up with assessment by a multidisciplinary committee (Phase 3). Diagnostic yield was assessed after Phases 1 and 2. Empirical diagnostic accuracy was measured for diagnoses according to the ESC guidelines after Phase 3. The diagnostic yield after Phase 1 (history taking) was 94.7% (95% CI: 91.1-97.0%, 250/264 patients) and increased to 97.0% (93.9-98.6%, 256/264 patients) after Phase 2. The overall diagnostic accuracy (as established in Phase 3) of the Phases 1 and 2 diagnoses was 90.6% (95% CI: 86.2-93.8%, 232/256 patients). No life-threatening conditions were missed. Three patients died, two unrelated to the cause of transient loss of consciousness, and one whom remained undiagnosed. A clinical work-up at a tertiary syncope unit using the ESC guidelines has a high diagnostic yield, accuracy, and safety. History taking (Phase 1) is the most important diagnostic tool. Autonomic function tests never changed the Phase 1 diagnosis but helped to increase the certainty of the Phase 1 diagnosis in many patients and yield additional diagnoses in patients who remained undiagnosed after Phase 1. Diagnoses were inaccurate in 9.4%, but no serious conditions were missed. This is adequate for clinical practice.


Cytologic aspects of an interesting case of medullary thyroid carcinoma coexisting with Hashimoto's thyroiditis.
Among primary thyroid neoplasms, papillary thyroid carcinoma (PTC) and primary thyroid lymphoma (PTL) are known to coexist and are pathogenetically linked with Hashimoto's thyroiditis (HT). However, HT occurring in association with medullary thyroid carcinoma (MTC) is rarely documented. We report here an interesting case. A 34-year-old female with a solitary thyroid nodule underwent fine needle aspiration cytology (FNAC) that was interpreted as "MTC with admixed reactive lymphoid cells, derived possibly from a pretracheal lymph node." Total thyroidectomy specimen showed "MTC with coexisting HT." At a later stage, a follow-up FNAC from the recurrent thyroid swelling showed features consistent with HT. As an academic exercise, the initial smears on which a diagnosis of MTC was offered were reviewed to look for evidence of coexisting HT that showed scanty and patchy aggregates of reactive lymphoid cells without Hürthle cells. Our case highlights an unusual instance of MTC in concurrence with HT that can create a tricky situation for cytopathologists.


[Detection of epidermal growth factor receptor gene mutations in non-small cell lung cancers by real-time polymerase chain reaction using scorpion amplification refractory mutation system].
To investigate mutations of EGFR gene in non-small cell lung cancers (NSCLC) using scorpions amplification refractory mutation system (Scorpions ARMS) is in comparing the detection sensitivity with that by PCR-direct sequencing method, and in addition to study the correlation between the mutations and the clinicopathological characteristics of the patients. Tumor cells were collected by microdissection from paraffin embedded tumor specimens and adjacent normal lung tissues of 82 NSCLC patients. The genomic DNA was extracted. Mutations of EGFR gene (exons 18, 19, 20 and 21) were detected by PCR-direct sequencing and Scorpions ARMS methods respectively. Somatic mutations were identified involving the tyrosine kinase domain of the EGFR gene in 42 of 82 cases with a mutation detection rate of 51.2% by Scorpions ARMS assay. In-frame deletions of exon 19 occurred in 20 patients and point mutation occurred at codon 858, 861 (exon 21) in 18 and 1 patients respectively. Two patients had insertions mutations and 1 patient had point mutation occurring at codon 768 (exon 20). Among the 58 informative cases analyzed by PCR-direct sequencing, 25 mutations (detection rate of 30.5%) were identified. In-frame deletions of exon 19 occurred in 13 patients and point mutation occurred at codon 858, 861 (exon 21) in 10 and 1 patients respectively. In addition, 1 patient had point mutation at codon 768 (exon 20). Overall, Scorpions ARMS assay was more sensitive in detecting mutations of EGFR than PCR-direct sequencing. A higher incidence of somatic mutations of EGFR gene was detected in NSCLC of Chinese patients. Mutations were more common in female, non-smoking patients with adenocarcinoma and bronchioloalveolar carcinoma histology. Scorpions ARMS method is quicker, more sensitive and accurate in detecting the EGFR gene mutations and should provide important therapeutic and prognostic information to the clinicians.


Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin.
Imbalanced matrix metalloproteinase (MMP) activity promotes cardiovascular alterations that are attenuated by statins. These drugs exert pleiotropic effects independent of cholesterol concentrations, including upregulation of nitric oxide (NO) formation and MMP downregulation. However, statins also increase tissue concentrations of nitrites, which activate new signaling pathways independent of NO. We examined whether atorvastatin attenuates MMP-9 production by human umbilical vein endothelial cells (HUVEC) stimulated with phorbol 12-myristate 13-acetate (PMA) by mechanisms possibly involving increased nitrite, and whether this effect results of NO formation. We also examined whether such an effect is improved by sildenafil, an inhibitor of phosphodiesterase-5 which potentiates NO-induced increases in cyclic GMP. MMP activity and nitrite concentrations were measured by gelatin zymography and ozone-based reductive chemiluminescence, respectively, in the conditioned medium of HUVECs incubated for 24 h with these drugs. Phospho-NFκB p65 concentrations were measured in cell lysate to assess NFκB activation. Atorvastatin attenuated PMA-induced MMP-9 gelatinolytic activity by mechanisms not involving NO, although it increased nitrite concentrations, whereas sildenafil had no effects. Combining both drugs showed no improved responses compared to atorvastatin alone. While sodium nitrite attenuated MMP-9 production by HUVECs, adding hemoglobin (NO scavenger) did not affect the responses to nitrite. Neither atorvastatin nor nitrite inhibited PMA-induced increases in phospho-NFκB p65 concentrations. These findings show that sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects exerted by atorvastatin. With both drugs, the inhibitory effects on MMP-9 production are not dependent on NO formation or on inhibition of NFκB activation. Our findings may help to elucidate important new nitrite-mediated mechanisms by which statins affect imbalanced MMP activity in a variety of cardiovascular disease.


Long-term, high level in vivo gene expression after electric pulse-mediated gene transfer into skeletal muscle.
Gene delivery to skeletal muscle is a promising strategy for the treatment of muscle disorders and for the local or systemic secretion of therapeutic proteins. However, current DNA delivery technologies have to be improved. We report very efficient luciferase gene transfer into muscle fibres obtained through the delivery of square-wave electric pulses of moderate field strength (100-200 V/cm) and of long duration (20 ms) to muscle previously injected with plasmid DNA. This intramuscular 'electrotransfer' method increases reporter gene expression by more than 100 times. It is noteworthy that this expression remains high and stable for at least 9 months. Moreover, intramuscular electrotransfer strongly decreases the interindividual variability usually observed after plasmid DNA injection into muscle fibres. Therefore, DNA electrotransfer in muscle possesses broad potential applications in gene therapy and for physiological, pharmacological and developmental studies.


Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat.
The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO-B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.