Injection therapy for subacute and chronic benign low back pain.
Injection with anaesthetics and/or steroids is one of the treatment modalities used in patients with chronic low back pain which needs evaluation with respect to the effectiveness on short and long term pain relief. To evaluate the effectiveness of injection therapy in patients with low back pain lasting longer than one month. We distinguished between three injection sites: facet joint, epidural or local injections. We searched the Medline and Embase databases up to 1996 and other search methods as advocated by the Back Review Group search strategy. Abstracts and unpublished studies were not included. Randomized controlled trials of injection therapy for pain relief (although additional treatments were allowed) in patients with benign low back pain lasting longer than one month and not originating from cancer. Two reviewers independently assessed the trials for methodological quality. Subgroup analyses were made between trials with different control groups (placebo and active injections), with different injection site (facet joint, epidural and local injection), and timing of outcome measurement (short and long term). Within the resulting 12 subcategories of studies (2*3*2), the overall relative risks and corresponding 95% confidence intervals were estimated, using a random effects model (DerSimonian and Laird). In the case of trials in which control groups were active injections, we refrained from pooling the results. Twenty-one randomized trials were included in this review. All studies involved patients with low back pain lasting longer than one month. Only 11 studies compared injection therapy with placebo injections (explanatory trials). The methodologic quality of many studies was low: only 8 studies had a methodologic score of 50 or more points. There were only three well designed explanatory clinical trials: one on injections into the facet joints with a short-term RR of 0.89 (95% CI: 0.65-1.21) and a long-term RR of 0.90 (95% CI: 0.69-1.17); one on epidural injections with a short-term RR of 0.94 (95% CI: 0.76-1.15) and a long-term RR of 1.00 (95% CI: 0.71-1.41); and one on local injections with a long-term RR of 0.79 (95% CI: 0.65-0.96). Within the 6 subcategories of explanatory studies the pooled RRs with 95% confidence intervals were: facet joint, short-term: RR=0.89 (0.65-1.21); facet joint, long-term: RR=0.90 (0.69-1.17); epidural, short-term: RR=0.93 (0. 79-1.09); epidural, long-term: RR=0.92 (0.76-1.11); local, short-term: RR=0.80 (0.40-1.59); local, long-term: RR=0.79 (0.65-0. 96). Convincing evidence is lacking on the effects of injection therapies for low back pain. There is a need for more, well designed explanatory trials in this field.


Knockdown of circ_0000512 Inhibits Cell Proliferation and Promotes Apoptosis in Colorectal Cancer by Regulating miR-296-5p/RUNX1 Axis.
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Increasing evidence showed that circular RNAs (circRNAs) played critical roles in the progression of CRC. However, the effects and underlying mechanisms of circ_0000512 in CRC progression remain unclear. The expression levels of circ_0000512, microRNA-296-5p (miR-296-5p) and runt-related transcription factor 1 (RUNX1) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, colony formation, cell cycle distribution and cell apoptosis were detected by Cell Counting Kit-8 (CCK-8) assay, colony formation assay and flow cytometry analysis, respectively. Western blot assay was utilized to measure the protein expression of Cyclin D1, Cleaved Caspase-3 and RUNX1. The interaction between miR-296-5p and circ_0000512 or RUNX1 was predicted by starBase and verified by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. The mice xenograft model was established to explore the function of circ_0000512 in vivo. The expression of circ_0000512 was increased in CRC tissues and cells. Knockdown of circ_0000512 suppressed cell viability and colony formation and arrested the cells at the G0/G1 phase while it accelerated apoptosis in CRC cells. Mechanistically, circ_0000512 could increase RUNX1 expression by acting as a molecular sponge of miR-296-5p in CRC cells. Furthermore, miR-296-5p downregulation or RUNX1 overexpression reversed the anti-proliferation and pro-apoptosis effects caused by circ_0000512 knockdown in CRC cells. In addition, circ_0000512 interference inhibited tumor growth by upregulating miR-296-5p and downregulating RUNX1 in vivo. Knockdown of circ_0000512 inhibited cell proliferation and induced apoptosis in CRC cell by regulating miR-296-5p/RUNX1 axis, which might provide a potential therapeutic target for CRC treatment.


Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton.
Neurofibromatosis 2 (NF2) protein (merlin; schwannomin) is a tumor suppressor involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas. The protein shares the domain structure of three homologous proteins: ezrin, radixin and moesin (ERM). ERM proteins function as membrane organizers and may act as linkers between plasma membrane molecules, such as CD44 and ICAM-2, and the cytoskeleton. We analyzed the distribution and effects of transfected NF2 protein in COS-1, CHO and 293 cells, and endogenous NF2 protein in U251 glioma cells. The distribution was compared to ezrin, CD44 and F-actin. Both transfected and endogenous NF2 protein localized underneath the plasma membrane in a pattern typical of an ERM protein. In COS-1 transfectants, NF2 protein typically codistributed with ezrin but, in cells with poorly developed actin cytoskeleton, it replaced ezrin in filopodia and ruffling edges. NF2 protein colocalized with CD44, which in transfected cells accumulated into restructured cell membrane protrusions. The association of CD44 and NF2 protein was further suggested by binding of CD44 from cellular lysates to recombinant NF2 protein. Interaction between NF2 protein and the actin-containing cytoskeleton was indicated by partial colocalization, by cytochalasin B-induced coclustering, and by retention of NF2 protein in the detergent-insoluble fraction. Transfected NF2 protein induced morphogenic changes. The cells contained restructured membrane extensions and blebs, and CHO cells expressing NF2 protein were more elongated than control transfectants. In conclusion, NF2 protein possesses functional properties of an ERM family member.


Utility of N-terminal pro-brain natriuretic peptide in detecting diastolic dysfunction in asymptomatic hypertensive patients: comparison with echocardiography.
Introduction: Data suggest that brain natriuretic peptide (BNP) and NT pro-BNP partially reflect ventricular pressure and could have a role in the early detection of diastolic abnormalities in hypertensive patients with normal systolic function. This study aimed to assess the role of NT pro-BNP for early detection of diastolic dysfunction in patients with hypertension and to correlate its level with echocardiographic parameters of diastolic dysfunction. Methods: This is a comparative cross-sectional study. Hundred cases of asymptomatic hypertensive patients with normal left ventricular (LV) systolic function and 100 healthy subjects were subjected to echocardiography and measurement of serum NT-pro BNP who received care at outpatient department of internal medicine, B.P. Koirala Institute of health sciences, Nepal. Results: Both systolic and diastolic blood pressures were significantly higher (≥160 and/or 100 mm Hg) in cases compared to controls (<120/80 mm Hg). Echocardiographic parameters of diastolic dysfunction: E/A ratio, E/E'ratio, deceleration time and isovolumetric relaxation time showed a significant difference between cases and controls. Mean serum NT-proBNP was significantly higher in patients with hypertension (213.19 ±184.3 pg/mL) compared to controls (58.51 ± 11.01 pg/mL) (P=0.008). There was no significant difference in mean serum NT-pro BNP levels between cases with no LV diastolic dysfunction (n=14) and controls (n=100) but it showed a significant difference between cases with LV diastolic dysfunction of all grades (n=86) and controls (n=100) (P=0.00). NT-proBNP levels were higher in both group of patients with E/A ratios <0.9 and 0.9-1.5 (245.72 ± 166.73 pg/mL and 210.69 + 143.53 pg/mL respectively) as compared to controls. Mean serum NT-proBNP levels were significantly higher in patients with IVRT >90 ms (270.43 ± 180.81 pg/mL) as compared to controls (P=0.03) but the difference was not significant between cases with IVRT of 60-90 ms (152.02 ± 100.23 pg/mL) and controls (P=0.09). NT-proBNP levels were significantly higher in all groups of patients with E/E' ratios <8, 8-12, >12 (197 ± 121.25 pg/mL, 263.12 ± 122.52 pg/mL and 180 ± 106.56 pg/mL respectively) compared to controls. Conclusion: Mean serum NT-proBNP was significantly higher in patients with hypertension as compared to controls. There is some correlation between echocardiographic parameters of diastolic dysfunction and serum NT-proBNP. Hence, NT-proBNP may be useful for early detection of LV diastolic dysfunction in patients with hypertension.


Electrochemical aptasensor based on the dual-amplification of G-quadruplex horseradish peroxidase-mimicking DNAzyme and blocking reagent-horseradish peroxidase.
A simple electrochemical aptasensor for sensitive detection of thrombin was fabricated with G-quadruplex horseradish peroxidase-mimicking DNAzyme (hemin/G-quadruplex system) and blocking reagent-horseradish peroxidase as dual signal-amplification scheme. Gold nanoparticles (nano-Au) were firstly electrodeposited onto single wall nanotube (SWNT)-graphene modified electrode surface for the immobilization of electrochemical probe of nickel hexacyanoferrates nanoparticles (NiHCFNPs). Subsequently, another nano-Au layer was electrodeposited for further immobilization of thrombin aptamer (TBA), which later formed hemin/G-quadruplex system with hemin. Horseradish peroxidases (HRP) then served as blocking reagent to block possible remaining active sites and avoided the non-specific adsorption. In the presence of thrombin, the TBA binded to thrombin and the hemin released from the hemin/G-quadruplex electrocatalytic structure, increasing steric hindrance of the aptasensor and decomposing hemin/G-quadruplex electrocatalytic structure, which finally decreased the electrocatalytic efficiency of aptasensor toward H(2)O(2) in the presence of NiHCFNPs with a decreased electrochemical signal. On the basis of the synergistic amplifying action, a detection limit as low as 2 pM for thrombin was obtained.


Comparison of perioperative outcomes and complications between intracorporeal, extracorporeal, and hybrid ileal conduit urinary diversion during robot-assisted radical cystectomy: a comparative propensity score-matched analysis from nationwide multi-institutional study in Japan.
To investigate the impact of different urinary diversion (UD) techniques on the peri- and postoperative complications of robot-assisted radical cystectomy (RARC) with ileal conduit. We retrospectively analyzed 373 patients undergoing RARC with ileal conduit at 11 institutions in Japan between April 2018 and December 2021. Propensity score weighting was performed to adjust for confounding factors such as age, sex, body mass index, performance status, American Society of Anesthesiologists score, previous abdominal surgery, neoadjuvant chemotherapy, and preoperative high T stage (≥ cT3) and high N stage (≥ cN1). Perioperative complications were then compared among three groups: extracorporeal, intracorporeal, and hybrid urinary diversion (ECUD, ICUD, and HUD, respectively). A total of 150, 68, and 155 patients received ECUD, HUD, and ICUD, respectively. Bowel reconstruction time and UD time were significantly shorter in the ECUD group (p < 0.001), and console time was significantly longer and blood loss was significantly higher in the ICUD group (p < 0.001). For postoperative complications (Clavien-Dindo Classification grade ≥ 3), surgical site infection (p = 0.004), pelvic abscess (p = 0.013), anastomotic urine leak (p = 0.007), and pelvic organ prolapse (p = 0.011) significantly occurred in the ECUD group. For all grades, ileus was more common in the HUD group, whereas anastomotic stricture was more common in the ECUD group compared with the other groups (p < 0.05). Severe complications did not increase after HUD and ICUD compared with ECUD; however, console time tended to be longer and blood loss was slightly higher during RARC.


3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle.
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures-namely the ER surface and the membranous webs-based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.


Coffee intake and risk of diabetic nephropathy: a Mendelian randomization study.
A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature of these associations. 40 independent single nucleotide polymorphisms (SNPs) associated with coffee intake were selected from the UK Biobank study. Summary-level data for diabetic nephropathy were obtained from publicly available genome-wide association studies (GWAS) and the FinnGen consortium. Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were used to examine a causal association. Sensitivity analyses included Cochran's Q test, the intercept of MR-Egger, MR-PRESSO, and the Outlier method. Leave-One-Out sensitivity analyses were also conducted to reduce the heterogeneity. Our current study demonstrated positive associations of genetically predicted coffee intake with diabetic nephropathy (OR=1.939; P = 0.045 and type 2 diabetes with renal complications (OR = 2.787, P= 0.047). These findings were robust across several sensitivity analyses. This study found a positive correlation between coffee consumption and the risk of diabetic nephropathy using genetic data. For a more accurate and trustworthy conclusion, subgroup analysis on coffee intake, including preparing method, variety of coffee, and quantity, is required.


Secretome analysis of Glioblastoma cell line--HNGC-2.
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary malignant tumor of the central nervous system. We have carried out a deep analysis of the secretome of a rapidly proliferating and tumorigenic cell line HNGC-2, representing GBM, in an effort to identify proteins, which may be targeted in the plasma of GBM patients as markers for diagnosis and disease surveillance. Prefractionation of the proteins from the conditioned medium of HNGC-2 cells in SDS gels followed by LC-MS/MS analysis using an ESI-IT mass spectrometer (LTQ) led to a total of 996 protein identifications with ≥2 peptides each. Of them, 664 proteins were observed in the transcriptome of HNGC-2 cells. The dataset of 996 proteins was mapped to important functional groups, such as cellular assembly and organisation, DNA recombination and repair, and other classes. Actin cytoskeleton signalling, phosphatidyl inositol 3 kinase (PI3K/AKT) and integrin linked kinase (ILK) signalling pathways were seen as enriched pathways. Comparisons with the published secretome of cell lines from 12 different cancers, including GBM, revealed that 348 proteins shared a commonality with a secretome of at least one other cell line, 321 of which were found to contain signal sequences or transmembrane domains and 335 could be linked to a plasma membrane or extracellular localization. Through intergration of this data we arrived at a non-redundant list of 597 protein identifications with the potential for secretion either by classical secretory pathways or by non-secretory processes; 233 of them have been detected in cerebrospinal fluid or plasma as per the published literature, and 172 have been implicated in GBM or other cancers. The HNGC-2 secretome dataset could serve as a useful resource for designing a targeted investigation of GBM biomarkers in plasma.


PEDF expression affects retinal endothelial cell proangiogenic properties through alterations in cell adhesive mechanisms.
Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis. Although various ocular cell types including retinal endothelial cells (EC) produce PEDF, we know very little about cell autonomous effects of PEDF in these cell types. Here we determined how PEDF expression affects retinal EC proangiogenic properties. Retinal EC were prepared from wild-type (PEDF+/+) and PEDF-deficient (PEDF-/-) mice. The identity of EC was confirmed by staining for specific markers including vascular endothelial cadherin, CD31, and B4-lectin. Retinal EC also expressed VEGF receptor 1 and endoglin, as well as ICAM-1, ICAM-2, and VCAM-1. PEDF-/- retinal EC were more proliferative, less apoptotic when challenged with H2O2, less migratory, and less adherent compared with PEDF+/+ EC. These changes could be associated, at least in part, with increased levels of tenascin-C, fibronectin, thrombospondin-1 and collagen IV, and lower amounts of osteopontin. PEDF-/- EC also exhibited alterations in expression of a number of integrins including α2, αv, β1, β8, and αvβ3, and cell-cell adhesion molecules including CD31, zonula occluden-1, and occludin. These observations correlated with attenuation of capillary morphogenesis and increased levels of oxidative stress in PEDF-/- EC. PEDF-/- EC also produced lower levels of VEGF compared with PEDF+/+ cells. Thus, PEDF deficiency has a significant impact on retinal EC adhesion and migration, perhaps through altered production of extracellular matrix and junctional proteins in response to increased oxidative stress affecting their proangiogenic activity.


Development of zebrafish paired and median fin musculature: basis for comparative, developmental, and macroevolutionary studies.
The model organism Dario rerio (zebrafish) is widely used in evo-devo and comparative studies. Nevertheless, little is known about the development and differentiation of the appendicular musculature in this fish. In this study, we examined the development of the muscles of all five zebrafish fin types (pectoral, pelvic, anal, dorsal and caudal). We describe the development of the muscles of these fins, including some muscles that were never mentioned in the literature, such as the interhypurales of the caudal fin. Interestingly, these caudal muscles are present in early stages but absent in adult zebrafishes. We also compare various stages of zebrafish fin muscle development with the configuration found in other extant fishes, including non-teleostean actinopterygians as well as cartilaginous fishes. The present work thus provides a basis for future developmental, comparative, evolutionary and evo-devo studies and emphasizes the importance of developmental works on muscles for a more comprehensive understanding of the origin, development and evolution of the appendicular appendages of vertebrate animals.


Effects of PPARγ agonistrosiglitazone on human retinoblastoma cell in vitro and in vivo.
The aim of the study was to evaluate the antitumor effects of the PPARγ agonist rosiglitazone on the human retinoblastoma. The cell biological behavior was detected, specifically, the effects of rosiglitazone on cell viability and apoptosis of the human retinoblastoma Y79 cells were investigated by MTT assay and Hochest 33258 staining and the migration assay showed that rosiglitazone blocked the invasion and migration of the carcinoma cells through the reconstituted extracellular matrix (Matrigel). The effect of rosiglitazone on NF-κB-dependent reporter gene transcription induced by LPS was analyzed by NF-κB-luciferase assay. Then human retinoblastoma Y79 cells were subcutaneously transplanted in BALB/c nude mice, and the animals were treated with rosiglitazone (20 mg/kg, 40 mg/kg, and 80 mg/kg) to verify its anti-tumor effect in vivo. Rosiglitazone suppressed the viability of Y79 cells dose- and time-dependently and induced apoptosis in Y79 cells in vitro. Molecular biology analysis found that rosiglitazone could modulate the proliferative and apoptosis related signal, reduce NF-κB-dependent reporter gene transcription induced by LPS. Rosiglitazone markedly reduced the growth of Y79 cells transplanted into the mice without causing significant side effects. Our results suggested that rosiglitazone demonstrated antitumor activity against the human retinoblastoma Y79 cells by inhibiting cell growth, inducing apoptosis and inhibiting metastasis and invasion in vitro and delaying tumor growth in vivo.


Chemical and sensory properties of liquid beet sugar.
Sensory analysis and headspace gas chromatography-flame ionization detection (GC-FID) analysis of liquid sugars (sucrose) designated for food-industrial use were performed in order to elucidate which compounds are responsible for perceived off-odors and off-flavors in liquid sugar. The liquid sugar samples investigated had various kinds of off-odors and off-flavors that might influence the quality of any food product in which they might be used, such as a jam or a soft drink. The sensory scores for the different attributes and the levels of different volatile compounds as measured by GC were analyzed for correlation using partial least-squares (PLS) analysis. A link between sensory analysis and GC analysis was thereby established, and compounds critical for the odor and flavor were identified using MS (mass spectrometry). Approximately 10 compounds were found to be correlated with the defined sensory attributes. Among these compounds associated with the sensory attributes were dimethyl disulfide, 2,6-dimethylpyrazine, 4-methoxyphenol, and 2, 5-dimethylfuran.


Recognizing Predictive Substructures with Subgraph Information Bottleneck.
The emergence of Graph Convolutional Network (GCN) has greatly boosted the progress of graph learning. However, two disturbing factors, noise and redundancy in graph data, and lack of interpretation for prediction results, impede further development of GCN. One solution is to recognize a predictive yet compressed subgraph to get rid of the noise and redundancy and obtain the interpretable part of the graph. This setting of subgraph is similar to the information bottleneck (IB) principle, which is less studied on graph-structured data and GCN. Inspired by the IB principle, we propose a novel subgraph information bottleneck (SIB) framework to recognize such subgraphs, named IB-subgraph. However, the intractability of mutual information and the discrete nature of graph data makes the objective of SIB notoriously hard to optimize. To this end, we introduce a bilevel optimization scheme coupled with a mutual information estimator for irregular graphs. Moreover, we propose a continuous relaxation for subgraph selection with a connectivity loss for stabilization. We further theoretically prove the error bound of our estimation scheme for mutual information and the noise-invariant nature of IB-subgraph. Extensive experiments on graph learning and large-scale point cloud tasks demonstrate the superior property of IB-subgraph.


The effect of morphine on regional cerebral blood flow measured by 99mTc-ECD SPECT in dogs.
To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points.


Functional impairments, fatigue and quality of life in RYR1-related myopathies: A questionnaire study.
Mutations in RYR1 are a common genetic cause of non-dystrophic neuromuscular disorders. To obtain baseline data concerning the prevalence of fatigue, the psychological disease burden and quality of life associated with these common conditions, we performed a questionnaire study. Seventy-two patients were included in this study, 33 with a congenital myopathy and 39 with malignant hyperthermia or exertional rhabdomyolysis. Our results showed that patients with RYR1-related myopathies have more functional impairments and significant chronic fatigue compared to healthy controls, with almost half of patients being severely fatigued. Whilst fatigue, pain and associated physical and social difficulties were more pronounced in those with permanent phenotypes, individuals with intermittent phenotypes also scored higher in all relevant categories compared to healthy controls. These findings indicate that RYR1-related myopathies, despite being often considered relatively mild conditions, are nevertheless associated with severe fatigue and functional limitations, resulting in substantial loss of quality of life. Moreover, milder but in essence similar findings in patients with RYR1-related malignant hyperthermia and rhabdomyolysis suggest that those phenotypes are not truly episodic but in fact associated with a substantial permanent disease burden. These preliminary data should help to design more comprehensive quality of life studies to inform standards of care.


Identification of cytotoxic T lymphocyte epitopes of human herpesvirus 8.
The human herpesvirus 8 (HHV-8) is a human gamma2-herpesvirus that is implicated in the development of Kaposi's sarcoma (KS), primary effusion lymphoma and Castelman's disease. Since the responses of cytotoxic T lymphocytes (CTL) play a key role in the control of herpesvirus infection, it is important to identify and to characterize the CTL target epitopes of HHV-8 viral antigens. In this study, using peptide-binding motifs, we selected potential human leucocyte antigen (HLA)-A2-binding peptides from kaposin A and glycoprotein H (gH), that are latent and lytic HHV-8 antigens, respectively. HLA-A2-binding peptides were tested for their capacity to induce CTL responses in HHV-8-negative healthy donors. By this approach, we found that the majority of individuals responded to two HHV-8-derived CTL epitopes, namely, VLLNGWRWRL (amino acids 16-25), which derives from kaposin A, and FLNWQNLLNV (amino acids 59-68), which derives from gH. In addition, memory CTL responses to these epitopes were detected in disease-free individuals infected by HHV-8 demonstrating that the two epitopes are relevant targets of CTL-mediated immunity in vivo. The identified epitopes may be investigated for the development of immunotherapeutic strategies against HHV-8-associated malignancies.


Dynamic change of mitral apparatus as potential cause of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.
the geometry of the mitral apparatus changes dynamically throughout systole and diastole. We investigated how geometric dynamics of the mitral apparatus could affect the haemodynamics of the outflow tract in patients with hypertrophic cardiomyopathy presenting with systolic anterior motion (HCM(SAM)) using three-dimensional (3D) echocardiography. we obtained transthoracic volumetric images in 21 patients with HCM(SAM) with differing trans-left ventricular (LV) outflow tract pressure gradient (PG(LVOT)) and in 23 controls. Original software was used to crop the 3D data into 18 radial planes; the mitral annulus, leaflets, coaptation point, protruding septum, and papillary muscles (PMs) tips were traced in each plane. The data were then reconstructed for 3D distance measurements and volumetric assessment. Shorter coaptation-septal distance (12 ± 4 vs. 21 ± 3 mm, P < 0.001), shorter inter-PM distance (13 ± 5 vs. 18 ± 4 mm, P = 0.02), and larger mitral tenting volume/body surface area (TVindex) (2.1 ± 1 vs. 0.5 ± 0.3 mL/m(2), P < 0.001) were associated with HCM(SAM) vs. control. PG(LVOT) increased with TVindex (r = 0.51, P = 0.01), and decreased with coaptation-septal distance(r = -0.83, P < 0.001) and the inter-PM distance (r = -0.69, P < 0.001) at mid-systole but not at mid-diastole (all P> 0.05). In addition, the coaptation-septal distance, TVindex, and inter-PM distance correlated each other (all P < 0.05). After adjustment for measures of mitral geometric change, the coaptation-septal distance was closely associated with PG(LVOT) (β = -0.73, P < 0.001). these findings suggest that dynamic geometric changes by interaction of PMs, mitral tenting, and the coaptation point at mid-systole may be important contributors to outflow obstruction in HCM(SAM).


Reprogramming of two induced pluripotent stem cell lines from a heterozygous GRIN2D developmental and epileptic encephalopathy (DEE) patient (BGUi011-A) and from a healthy family relative (BGUi012-A).
The GLUN2D subunit of the N-methylD-aspartate receptor (NMDAR) is encoded by the GRIN2D gene. Mutations in GRIN2D have been associated with neurodevelopmental and epileptic encephalopathies. Access to patient samples harboring mutations in GRIN2D can contribute to understanding the role of NMDAR in neuronal development and function. We report the generation of induced pluripotent stem cell (iPSC) lines from a GRIN2D-developmental and epileptic encephalopathy (DEE) patient, carrying a de novo c.1999G>A heterozygous pathogenic variant, and his healthy parent. Generated lines highly expressed pluripotency markers, spontaneously differentiated into the three germ layers, retained the deficiency-causing mutation, and displayed normal karyotypes.


Isolation and characterization of a specific endogenous Na+,K+-ATPase inhibitor from bovine adrenal.
In order to identify a specific endogenous Na+,K+-ATPase inhibitor which could possibly be related to salt-dependent hypertension, we looked for substances in the methanol extract of bovine whole adrenal which show all of the following properties: (i) inhibitory activity for Na+,K+-ATPase; (ii) competitive displacing activity against [3H]ouabain binding to the enzyme; (iii) inhibitory activity for 86Rb uptake into intact human erythrocytes; and (iv) cross-reactivity with sheep anti-digoxin-specific antibody. After stepwise fractionation of the methanol extract of bovine adrenal glands by chromatography on a C18 open column, a 0-15% acetonitrile fraction was fractionated by high-performance liquid chromatography on a Zorbax octadecylsilane column. One of the most active fractions in 0-15% acetonitrile was found to exhibit all of the four types of the activities. It was soluble in water and was distinct from various substances which have been known to inhibit Na+,K+-ATPase such as unsaturated free fatty acids, lysophosphatidylcholines, vanadate, dihydroxyeicosatrienoic acid, dehydroepiandrosterone sulfate, dopamine, lignan, ascorbic acid, etc. This substance was further purified by using an additional five steps of high-performance liquid chromatography with five different types of columns. Molecular mass was estimated as below 350 by fast atom bombardment mass spectroscopy and ultrafiltration. Heat treatment at 250 degrees C for 2 h and acid treatment with 6 N HCl at 115 degrees C for 21 h almost completely destroyed the inhibitory activity of the purified substance for Na+ pump activity. Additionally, alkaline treatment with 0.2 N NaOH at 23 degrees C for 2 h destroyed approximately 70% of the inhibitory activity, whereas boiling for 10 min and various enzyme digestion did not destroy the activity. The dose dependency for the four types of the activities for this substance paralleled those of ouabain, spanning 2 orders of magnitude in concentration range. The inhibitory potencies of the purified substance for Na+,K+-ATPase, Na+ pump, and ouabain binding activities were diminished with increasing K+ concentration, exhibiting a characteristic typical of cardiac glycosides. This substance had no effect on the Ca2+-ATPase activity or the Ca2+ loading rate into the vesicle prepared from skeletal muscle sarcoplasmic reticulum. These results strongly suggest that this water-soluble nonpeptidic Na+,K+-ATPase inhibitor may be a specific endogenous regulator for the ATPase.


Asymmetrical lipomatosis: report of two cases.
We report on two patients with an asymmetrical expansion of fat tissue. At computed tomography, lipomatous tissue proved to be superficially located in one patient and both subcutaneously and deeply located in the second. Signs and symptoms of a peripheral neuropathy were observed in both patients, who were otherwise asymptomatic. The lipolytic activity in post-heparin plasma was normal in both patients. The fat cell size of lipomatous tissue, obtained in one patient by percutaneous needle biopsy, was higher than that of contralateral, uninvolved adipose tissue. The adipose tissue lipoprotein lipase activity in lipomatous tissue was higher than that in normal tissue. High density lipoprotein (HDL), HDL2 and HDL3 cholesterol values were elevated in both patients but not exceeding 1 standard deviation the values of age and sex matched controls. Isoprenaline-stimulated lipid mobilization was similar in lipomatous and in control tissue.


3D reconstruction of small bowel lesions using stereo camera-based capsule endoscopy.
Three-dimensional (3D) reconstruction of capsule endoscopic images has been attempted for a long time to obtain more information on small bowel structures. Due to the limited hardware resources of capsule size and battery capacity, software approaches have been studied but have mainly exhibited inherent limitations. Recently, stereo camera-based capsule endoscopy, which can perform hardware-enabled 3D reconstruction, has been developed. We aimed to evaluate the feasibility of newly developed 3D capsule endoscopy in clinical practice. This study was a prospective, single-arm, feasibility study conducted at two university-affiliated hospitals in South Korea. Small bowel evaluation was performed using a newly developed 3D capsule endoscope for patients with obscure gastrointestinal bleeding, suspected or established Crohn's disease, small bowel tumors, and abdominal pain of unknown origin. We assessed the technical limitations, performance, and safety of the new capsule endoscope. Thirty-one patients (20 men and 11 women; mean age: 44.5 years) were enrolled. There was no technical defect preventing adequate visualization of the small bowel. The overall completion rate was 77.4%, the detection rate was 64.5%, and there was no capsule retention. All capsule endoscopic procedures were completed uneventfully. In conclusion, newly developed 3D capsule endoscopy was safe and feasible, showing similar performance as conventional capsule endoscopy. Newly added features of 3D reconstruction and size measurement are expected to be useful in the characterization of subepithelial tumours.


Predictors of 30-year mortality in depressed and comparison samples.
Although higher rates of depression and lower rates of social behaviors (i.e., social support and activities) and physical activities are associated with mortality, the independent contribution of each of these factors needs examination. A prospective sample of 848 individuals (55% female) was used; half were clinically depressed at baseline; the other half comprised a comparison sample matched on census tract, gender, and marital status. Depressive symptoms, social behaviors, and physical activities were examined as time-varying predictors of mortality over a 30-year period using multiple imputation for missing data and Cox proportional hazards regression, controlling for demographic factors and health risk factors. By the end of the study, 137 individuals from the depressed sample and 99 individuals from the comparison sample had died. Although the mortality rate is higher in the depressed sample, after controlling for demographic, health risk factors, social behaviors, and physical activity, there was no significant difference in mortality between the depressed and control samples. Among participants in the depressed sample, reduced participation in social activities was significantly associated with a higher risk of mortality. Frequency and intensity of activities were not assessed and all data except for mortality were self-report. Promoting social engagement through activities may hold promise for delaying mortality among individuals who are depressed. Potential methods to promote social engagement and factors such as positive emotions that should be considered in future studies are discussed.


Nitric oxide production occurs after cytosolic alkalinization during stomatal closure induced by abscisic acid.
Abscisic acid (ABA) raised the cytosolic pH and nitric oxide (NO) levels in guard cells while inducing stomatal closure in epidermis of Pisum sativum. Butyrate (a weak acid) reduced the cytosolic pH/NO production and prevented stomatal closure by ABA. Methylamine (a weak base) enhanced the cytosolic alkalinization and aggravated stomatal closure by ABA. The rise in guard cell pH because of ABA became noticeable after 6 min and peaked at 12 min, while NO production started at 9 min and peaked at 18 min. These results suggested that NO production was downstream of the rise in cytosolic pH. The ABA-induced increase in NO of guard cells and stomatal closure was prevented by 2-phenyl-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (cPTIO, a NO scavenger) and partially by N-nitro-L-Arg-methyl ester (L-NAME, an inhibitor of NO synthase). In contrast, cPTIO or L-NAME had only a marginal effect on the pH rise induced by ABA. Ethylene glycol tetraacetic acid (EGTA, a calcium chelator) prevented ABA-induced stomatal closure while restricting cytosolic pH rise and NO production. We suggest that during ABA-induced stomatal closure, a rise in cytosolic pH is necessary for NO production. Calcium may act upstream of cytosolic alkalinization and NO production, besides its known function as a downstream component.


Evidence for a partially structured state of the amylin monomer.
Islet amyloid polypeptide (amylin) is the main component in amyloid deposits formed in type II diabetes. We used triplet quenching to probe the dynamics of contact formation between the N-terminal disulfide loop and a C-terminal tryptophan in monomeric amylins from human and rat. Quenching rates measured in the absence of denaturant are four times larger than those in 6 M guanidinium chloride, indicating a decrease in the average end-to-end distance (collapse) at low denaturant concentrations. We were surprised to find an even greater (sevenfold) increase in quenching rates on removal of denaturant for a hydrophilic control peptide containing the disulfide loop compared to the same peptide without the loop (twofold change). These results suggest that collapse is driven by backbone-backbone and backbone-side chain interactions involving the disulfide loop portion of the chain rather than by the formation of side-chain hydrophobic contacts. Molecular dynamics simulations of the control peptide show that the collapse results from hydrogen-bonding interactions between the central residues of the chain and the disulfide loop. The quenching experiments also indicate that the monomer of the human, amyloidogenic form of amylin is more compact than the rat form, which does not form amyloid. We discuss these newly observed differences between human and rat amylin in solution and their possible relation to aggregation and to the physiological function of amylin binding to the calcitonin receptor.


Alcohol use and abuse and motivations for drinking and non-drinking among Spanish adolescents: do we know enough when we know parenting style?
Objective: We examine parenting styles (characterized by warmth and strictness, i.e., neglectful, indulgent, authoritarian and authoritative) as either a protective or risk factor for adolescence drinking.Design: Two 4 × 2 × 3 multi-factorial MANOVAs. Sample consisted of 996 underage Spanish adolescents, 532 males (53.4%), ranging from 15 to 17 years old.Main outcome measures: Alcohol use (wine, beer, mixed drinks and liquors) and abuse and motivations for drinking (social acceptance and self-enhancement) and non-drinking (harsh preventive rules and awareness of alcohol's harmful effects).Results: Lower risk of alcohol use and abuse was found in adolescents with indulgent parenting, and higher risk for adolescents with authoritarian parenting. Adolescents from indulgent parenting style homes had equal adjustment (lower self-enhancement and higher harsh preventive rules and awareness of alcohol's harmful effects) or even better (lower social acceptance) than those from authoritative parenting style homes. Consistently, the highest risk parenting styles identified were the authoritarian and neglectful styles (α=.05).Conclusion: At least in some cultures, warmth and reasoning, shared by authoritative and indulgent parenting styles, seem the recommended way to protect offspring from drinking. Effective alcohol prevention and intervention programs should include strategies tailored specifically to this new cultural context where parenting takes place.


Decontamination of unpackaged and vacuum-packaged boneless chicken breast with pulsed ultraviolet light.
The effectiveness of pulsed UV light on the microbial load of boneless chicken breast was investigated. Unpackaged and vacuum-packaged samples inoculated with an antibiotic-resistant strain of Salmonella Typhimurium on the top surfaces were treated with pulsed UV light for 5, 15, 30, 45, and 60 s at 5, 8, and 13 cm distance from the quartz window in the pulsed UV light chamber. The log(10) reductions of Salmonella (cfu/cm(2)) on unpackaged samples varied from 1.2 to 2.4 after a 5-s treatment at 13 cm and a 60-s treatment at 5 cm, respectively. The log(10) reductions on vacuum-packaged samples varied from 0.8 to 2.4 after the 5-s treatment at 13 cm and the 60-s treatment at 5 cm, respectively. The optimum treatment conditions were determined to be 5 cm-15 s for unpackaged samples and 5 cm-30 s for vacuum-packaged samples, both of which resulted in about 2 log(10) reduction (approximately 99%). The total energy and temperatures of samples increased with longer treatment time and shorter distance from the quartz window in the pulsed UV light chamber. The changes in chemical quality and color of samples were determined after mild (at 13 cm for 5 s), moderate (at 8 cm for 30 s), and extreme (at 5 cm for 60 s) treatments. Neither malonaldehyde contents nor color parameters changed significantly (P > 0.05) after mild and moderate treatments. Mechanical properties of the packaging material were analyzed before and after pulsed UV light treatments. The elastic modulus at both along-machine and perpendicular-to-machine direction and yield strength at perpendicular-to-machine direction changed significantly (P < 0.05) after extreme treatment. Overall, these results clearly indicate that pulsed UV light has a potential to be used for decontamination of unpackaged and vacuum-packaged poultry.


Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment.
Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1-3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored.


Cannabis and Inflammation in HIV: A Review of Human and Animal Studies.
Persistent inflammation occurs in people with HIV (PWH) and has many downstream adverse effects including myocardial infarction, neurocognitive impairment and death. Because the proportion of people with HIV who use cannabis is high and cannabis may be anti-inflammatory, it is important to characterize the impact of cannabis use on inflammation specifically in PWH. We performed a selective, non-exhaustive review of the literature on the effects of cannabis on inflammation in PWH. Research in this area suggests that cannabinoids are anti-inflammatory in the setting of HIV. Anti-inflammatory actions are mediated in many cases through effects on the endocannabinoid system (ECS) in the gut, and through stabilization of gut-blood barrier integrity. Cannabidiol may be particularly important as an anti-inflammatory cannabinoid. Cannabis may provide a beneficial intervention to reduce morbidity related to inflammation in PWH.


Neuroendocrine markers in adenocarcinomas: an investigation of 356 cases.
To investigate the incidence of neuroendocrine (NE) cells and their hormone products in adenocarcinomas and evaluate their significance in clinical pathology and prognosis. By using tissue sectioning and immunocyto-chemistry, 356 cases of adenocarcinomas were studied to examine the presence of chromorgranin and polypeptide hormones in adenocarcinoma samples from our hospital. The positive rate of NE cells and hormone products was 41.5 % (54/130) and 59.3 % (32/54), respectively in large intestinal adenocarcinoma cases; 39.6 % (38/96) and 36.8 % (14/38), respectively in gastric cancer cases; 38.1 % (8/21) and 50.0 % (4/8), respectively in prostatic cancer cases; 21.0 % (17/81) and 17.6 % (3/17), respectively in breasr cancer cases; 17.9 % (5/28) and 60.0 % (3/5), respectively in pancreatic cancer cases. Among carcinomas of large intestine, pancreas and breast, the highly differentiated NE cell numbers were higher than the poorly differentiated NE cell numbers; while the gastric carcinoma cases had more poorly differentiated NE cells than highly differentiated NE cells. The higher detection rate of NE cells and their hormone products, the higher 5-year survival rate among the large intestine cancer cases. Close correlation was observed between NE cells and their hormone products with the cancer differentiations. For colorectal carcinomas, there is a close correlation of the presence of NE cells and their hormone products with the tumor staging and prognosis.


Nutrition programmes for individuals living with disadvantage in supported residential settings: a scoping review.
Health inequities such as chronic disease are significantly higher among individuals living with disadvantage compared with the general population and many are reported to be attributable to preventable dietary risk factors. This study provides an overview of the current nutrition interventions for individuals living with extreme disadvantage, in supported residential settings, to develop insights into the development and implementation of policies and practices to promote long-term nutritional health and well-being. A scoping review searched Scopus, ProQuest, CINAHL Plus, MEDLINE, and Web of Science databases using the terms 'resident', 'nutrition', 'disadvantage', 'intervention' and their synonyms, with particular emphasis on interventions in residential settings. Residential services providing nutrition provision and support. People experiencing extreme disadvantage. From 5262 articles, seven were included in final synthesis. Most interventions focused on building food literacy knowledge and skills. Study designs and outcome measures varied; however, all reported descriptive improvements in behaviour and motivation. In addition to food literacy, it was suggested that interventions need to address behaviour and motivations, programme sustainability, long-term social, physical and economic barriers and provide support for participants during transition into independent living. Socio-economic issues remain key barriers to long-term health and well-being. In addition to food literacy education, future research and interventions should consider utilising an academic-community partnership, addressing nutrition-related mental health challenges, motivation and behaviour change and a phased approach to improve support for individuals transitioning into independent living.


[The use of Aedes albopictus C6/36 cells in the propagation and classification of arbovirus of the Togaviridae, Flaviviridae, Bunyaviridae and Rhabdoviridae families].
C6/36 Aedes albopictus cells were infected with Brazilian arbovirus from the families Togaviridae, Flaviviridae, Bunyaviridae and Rhabdoviridae. Replication was obtained with all the studied viruses and cytopathic effect was observed with some. Viral antigen was assayed in C6/36 cell cultures for antigen was assayed in C6/36 cells by an indirect immunofluorescence test using specific mouse immune ascitic fluid. Antigen production was detected in C6/36 cells infected with all the studied viruses. The author recommends the inoculation of C6/36 cell cultures for isolation of virus from the four studied families. The immunofluorescence technique is an important tool for classification and identification of virus growing in C6/36 cells.


Elevated Serum and Cerebrospinal Fluid CD138 in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.
CD138 (also known as syndecan-1) is an important component of endothelial cell glycocalyx, and it is reportedly involved in negative regulation of various inflammatory processes. The clinical implications of circulating and cerebrospinal fluid (CSF) soluble CD138 (sCD138) in patients with Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis remain unclear. The aim of the current study was to investigate associations between serum and CSF sCD138 levels in anti-NMDAR encephalitis patients. The participants enrolled in the study included 27 with anti-NMDAR encephalitis, 11 with viral meningoencephalitis, and 22 controls. At acute stage and 3 to 6-month follow-up time-points, sCD138, tumor necrosis factor-α, matrix metalloproteinase-2, and matrix metalloproteinase-9 in serum and CSF were measured in all participants via enzyme-linked immunosorbent assays. Serum and CSF levels of sCD138 were significantly increased in patients with anti-NMDAR encephalitis. Furthermore, after 3-6 months of follow-up CSF sCD138 levels were significantly decreased in anti-NMDAR encephalitis patients. Changes in sCD138 levels were significantly associated with amelioration of modified Rankin Scale scores in patients with anti-NMDAR encephalitis. In anti-NMDAR encephalitis patients, high circulating, and CSF sCD138 is associated with inflammation and poor clinical prognosis. The present study suggests that sCD138 may be an informative biomarker of inflammation in anti-NMDAR encephalitis.


Cortical atrophy in Parkinson disease: correlation between clinical and CT findings with special emphasis on prefrontal atrophy.
Thirty-seven patients with Parkinson disease were evaluated clinically and with computed tomography in order to determine the incidence of prefrontal atrophy. An age-matched healthy control group was also scanned. The computed tomographic criteria used were the width of cortical sulci and ventriculocerebral indices. Parkinsonian patients with frontal cortical atrophy represent only one patient out of three. They are much older than parkinsonian patients with normal computed tomographic scans, and the onset of their illness occurs later. No significant difference was found according to gender, parkinsonian clinical triad, psychomotor study, or mean duration of illness and/or dopatherapy to the time of computed tomography. This work seems to separate two Parkinson diseases: one beginning before 65 years and damaging the nigrostriate system, and another beginning after 65 years and damaging both the nigrostriate system and the cortex, particularly the frontal cortex.


Role of a binary metallic modifier in the determination of cadmium in graphite furnace atomic absorption spectrometry.
In order to discuss the matrix modifier effect of palladium, iron, and a mixture of palladium and iron for the determination of cadmium in graphite-furnace atomic absorption spectrometry (GF-AAS), we measured the absorption profiles of a cadmium line at various compositions of these elements. Variations in the gas temperature were also estimated with the progress of atomization, by using a two-line method under the assumption of a Boltzmann distribution. The atomic absorption of cadmium appeared on the way of heating from the charring temperature to the atomizing temperature while the gas temperature was still low; it was thus considered that cadmium was atomized through direct conductive heating from the wall of the graphite furnace. Therefore, the effectiveness of modifiers for cadmium would be determined through any reactions on the furnace wall at the programmed charring and atomizing temperatures. The addition of iron, palladium, and an iron-palladium mixture all enhanced the absorption signal of cadmium compared to a pure cadmium sample; however, their effects were different from one another. Each addition of iron or palladium to the sample solution led to an enhancement of the cadmium absorbance, indicating that iron or palladium individually became an effective matrix modifier for the determination of cadmium. However, the addition of palladium was ineffective for the matrix modification in the coexistence of large amounts of iron. Although these phenomena are very complicated, and thus cannot be understood completely, any metallurgical reaction between the constituent elements during heating of the furnace wall, such as the formation of solid solutions and intermetallic compounds, would cause the effect of a matrix modifier in GF-AAS.


Lichen planus secondary complications associated with the use of biologic therapy for rheumatoid arthritis.
Biologic therapy such as Etanercept, which is a tumor necrosis factor alpha (TNF-α) inhibitor, has been extensively used as election therapy in rheumatoid arthritis. The purpose of this case presentation was to inform about the possibility that lichen planus lesions could potentially become complicated by secondary infections in patients treated with Etanercept. Furthermore, we aimed at analyzing if the complication of the cutaneous lesion was coincidental or it was due to the immunosuppressive systemic therapy, and whether the infected lesion would respond to antibiotic therapy. The patient was a 59-year-old woman with rheumatoid arthritis and that have had lichen planus lesions for approximately 25 years. Only recently, she had been received immunosuppressive therapy (Etanercept and Methotrexate). Further on, the lichen planus flared up with a secondary infection determined by a Methicillin-sensitive Staphylococcus aureus. Uncommon myocardial complications were also characteristic of this case. While a case report described already the appearance of lichen planus following Etanercept therapy (Battistella M et al., 2008), the possibility that the lesion could become secondary complicated following this therapy was never reported before, according to our knowledge. Additionally, we describe in this case the interplay between Etanercept therapy and hypertrophic cardiomyopathy. Our case is not a lichen planus induced by Etanercept, but it is aggravated and secondary infected with Methicillin-sensitive Staphylococcus during the therapy. The additional cardiac complication (hypertrophic cardiomyopathy) may represent solely an evolutive sign of rheumatoid arthritis and therefore not influenced by Etanercept.


Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]).
Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients. Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction. Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC-treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC-treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy. Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs. URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.


Preparation of antimicrobial compounds by hydrolysis of oleuropein from green olives.
Oleuropein, an intensely bitter glucoside, was isolated from green olives. Hydrolysis products obtained from oleuropein in sufficient quantity for further tests were: (i) beta-3,4-dihydroxyphenylethyl alcohol prepared by acid hydrolysis of oleuropein; (ii) elenolic acid obtained by methanolysis of oleuropein, isolation of the intermediate acetal, and subsequent acid hydrolysis; and (iii) oleuropein aglycone formed by the action of beta-glucosidase on the parent glucoside. Mass spectral verification of the isolated compounds and ultraviolet absorption data are given. Oleuropein and its aglycone had similar threshold levels for detection of bitterness, whereas elenolic acid and beta-3,4-dihydroxyphenylethyl alcohol were not judged to be bitter.


Binding of insulin-like growth factors to Tera-2 human embryonal carcinoma cells during differentiation.
Differentiation of Tera-2 human embryonal carcinoma cells by exposure to 2.1 mM alpha-difluoromethylornithine resulted in changes in morphology, a decrease in growth rate, and changes in the expression of SSEA-1 differentiation antigen. While the binding of 125I-insulin-like growth factor I (IGF-I) remained relatively constant during differentiation, binding of 125I-IGF-II increased 2-3-fold. Further, the binding of IGF-II was 87 times greater than IGF-I in both undifferentiated and differentiated cells. Undifferentiated Tera-2 cells exhibited a single class of binding sites for both IGF-I (KD = 1.2 nM, 7.0 x 10(3) sites/cell) and IGF-II (KD = 8.3 nM, 3.4 x 10(5) sites/cell). Following differentiation, IGF-I continued to bind to a single class of binding sites (KD 1.0 nM, 6.7 x 10(3) sites/cell) whereas IGF-II bound to both high-affinity sites (KDH 0.3 nM, 2.2 x 10(5) sites/cell) and low-affinity sites (KDL 15.1 nM, 1.6 x 10(7) sites/cell). The binding of iodinated IGF-II was blocked by unlabeled IGF-II but not IGF-I. In contrast, 125I-IGF-I binding was prevented by either IGF-I or IGF-II. Affinity cross-linking experiments demonstrated the presence of both type I and type II IGF receptors along with a number of IGF binding proteins. IGF-I failed to stimulate the incorporation of [3H]thymidine in both undifferentiated and differentiated cells. Although IGF-II caused a significant increase in [3H]thymidine incorporation in both undifferentiated and differentiated Tera-2 cells, the magnitude of the response and the sensitivity of the cells to IGF-II stimulation was diminished following differentiation. The observed changes in IGF-II binding, which occur in conjunction with cellular differentiation, may be an important feature of the expression of the differentiated phenotype by human germ cell tumors.


Investigating the influence of elongated anaerobic feeding strategy on aerobic sludge granulation and characteristics in sequencing batch reactor.
In this research, two sequencing batch reactors (R1 and R2) were operated with different feeding strategies to investigate the effects of elongated anaerobic feeding mode on the granulation process. For this purpose, R1 was operated in a short-feed strategy (5 min) as a reference, whereas an extended anaerobic feeding of 85 min was applied in R2. Results showed that aerobic granules formed in R1 were denser and more uniform with lower sludge volume index than those formed in R2. Investigation of tightly bound extracellular polymeric substances (TB-EPS) showed that aerobic granules in R1 produced lower amounts of TB-EPS than those in R2. This was due to the bigger and more compact granules cultivated in R1 in comparison with looser structure granules in R2 with higher flocculent sludge percentage. The relative hydrophobicity of granules in both reactors was increased with culture time and reached about 63 and 65% at day 70 for R1 and R2, respectively. Moreover, no significant correlation between protein/polysaccharide ratio and hydrophobicity was found, which showed that protein in loosely bound extracellular polymer substances was not the predominant hydrophobic component. Considering the outcomes of this study, it can be concluded that the elongated anaerobic feeding strategy was unfavourable for cultivating aerobic granules.


Clinical, radiographic, and histologic evaluation of human periodontal defects treated with Bio-Oss and Bio-Gide.
This study evaluated the clinical, radiographic, and histologic response to Bio-Oss porous bone mineral when used alone or in combination with Bio-Gide bilayer collagen membrane in human periodontal defects. Four intrabony periodontal defects were treated: two received Bio-Oss alone and two were treated with a combination of Bio-Oss and Bio-Gide. Radiographs, clinical probing depths and attachment levels were obtained preoperatively and 6 to 9 months postoperative, and teeth and surrounding tissues were biopsied. Both treatments significantly improved clinical probing depths and attachment levels, and the radiographic appearance suggested osseous fill. Histologic evaluation revealed that both treatments produced new cementum with inserting collagen fibers and new bone formation on the surface of the graft particles; this regenerative effect was more pronounced using the Bio-Oss/Bio-Gide combination, which resulted in 7 mm of new cementum and periodontal ligament and extensive new bone incorporating the graft. The membrane was intact at 7 months and partially degraded by 9 months after treatment. This human histologic study demonstrates that the porous bone mineral matrix used has the capacity to stimulate substantial new bone and cementum formation and that this capacity is further increased when the graft is used with a slowly resorbing collagen membrane.


[Psychological-sociological views on S 218 (study on 379 pregnant women and women in puerperium)].
Studies on the attitude towards the abortion law and abortion have practical significance if women in the reproductive age group are questioned. Pregnant women and women in childbed are especially adequate for this purpose. They may realize best the situation of a women who has to think over an abortion. Therefore we asked 379 pregnant women and women in childbed in our hospital. 70% of them could imagine a situation which would justify an abortion. Women with high school degree and average or above average intelligence were more frequent in this group. 38% expected a very severe stress by an abortion, 40% severe stress and 22% a rather moderate one. Most frequently women with high education level as well as more introverted women expected an emotional disturbance by such an operation. 62% of the questioned women favored a change of the abortion law, 38% did not. Again women with high school degree and above average intelligence wanted a change more often than those who had passed primary school and had an intelligence below average. Moreover age, wellbeing and experience of menarche had a relation to the attitude towards the abortion law. The results were statistically checked by the X2 -method.


Regulation of cardiac excitation-contraction coupling by sorcin, a novel modulator of ryanodine receptors.
Activation of Ca2+ release channels/ryanodine receptors (RyR) by the inward Ca2+ current (I(Ca)) gives rise to Ca(2+)-induced Ca2+ release (CICR), the amplifying Ca2+ signaling mechanism that triggers contraction of the heart. CICR, in theory, is a high-gain, self-regenerating process, but an unidentified mechanism stabilizes it in vivo. Sorcin, a 21.6 kDa Ca(2+)-binding protein, binds to cardiac RyRs with high affinity and completely inhibits channel activity. Sorcin significantly inhibits both the spontaneous activity of RyRs in quiescent cells (visualized as Ca2+ sparks) and the I(Ca)-triggered activity of RyRs that gives rise to [Ca2+]i transients. Since sorcin decreases the amplitude of the [Ca2+]i transient without affecting the amplitude of I(Ca), the overall effect of sorcin is to reduce the "gain" of excitation-contraction coupling. Immunocytochemical staining shows that sorcin localizes to the dyadic space of ventricular cardiac myocytes. Ca2+ induces conformational changes and promotes translocation of sorcin between soluble and membranous compartments, but the [Ca2+] required for the latter process (ED50 = approximately 200 microM) appears to be reached only within the dyadic space. Thus, sorcin is a potent inhibitor of both spontaneous and I(Ca)-triggered RyR activity and may play a role in helping terminate the positive feedback loop of CICR.


Systematic review of electronic surveillance of infectious diseases with emphasis on antimicrobial resistance surveillance in resource-limited settings.
Electronic surveillance of infectious diseases involves rapidly collecting, collating, and analyzing vast amounts of data from interrelated multiple databases. Although many developed countries have invested in electronic surveillance for infectious diseases, the system still presents a challenge for resource-limited health care settings. We conducted a systematic review by performing a comprehensive literature search on MEDLINE (January 2000-December 2015) to identify studies relevant to electronic surveillance of infectious diseases. Study characteristics and results were extracted and systematically reviewed by 3 infectious disease physicians. A total of 110 studies were included. Most surveillance systems were developed and implemented in high-income countries; less than one-quarter were conducted in low-or middle-income countries. Information technologies can be used to facilitate the process of obtaining laboratory, clinical, and pharmacologic data for the surveillance of infectious diseases, including antimicrobial resistance (AMR) infections. These novel systems require greater resources; however, we found that using electronic surveillance systems could result in shorter times to detect targeted infectious diseases and improvement of data collection. This study highlights a lack of resources in areas where an effective, rapid surveillance system is most needed. The availability of information technology for the electronic surveillance of infectious diseases, including AMR infections, will facilitate the prevention and containment of such emerging infectious diseases.


Identification of the lymphokine soluble immune response suppressor in urine of nephrotic children.
Patients with minimal change nephrotic syndrome (MCNS) frequently have suppressed in vivo and in vitro immune responsiveness of uncertain etiology. Because increased suppressor cell activity has been associated with this disease, urines from MCNS patients were screened for activity of the lymphokine soluble immune response suppressor (SIRS), a product of concanavalin A- or interferon-activated suppressor T cells. Urines from untreated MCNS patients suppressed polyclonal plaque-forming cell responses of cultured splenocytes. This suppressive activity was identified as human SIRS by the following functional and physical criteria: molecular weight estimated by gel filtration; kinetics of suppression; inhibition of suppression by catalase, levamisole, and 2-mercaptoethanol; abrogation of activity by acid or protease treatment; elution pattern on high performance liquid chromatography; and cross-reactivity with monoclonal antimurine SIRS antibodies. Suppressive activity disappeared from urine after initiation of treatment but before remission of symptoms. Urines were tested from 11 patients with MCNS, all of whom excreted SIRS. In addition, two nephrotic patients with acute glomerulonephritis and three nephrotic patients with membranoproliferative disease excreted SIRS, but other nephrotics and all nonnephrotic patients did not. These results indicate that excretion of SIRS occurs in certain cases of nephrotic syndrome and that the presence of SIRS in the urine is not accounted for solely by the presence of proteinuria or nephrosis. Serum from four nephrotic patients also contained SIRS, whereas neither serum nor urine from six normal subjects contained SIRS activity. The systemic presence of SIRS in these four patients, and the identification of SIRS in urines from a larger group of patients, suggest a possible role for SIRS in the suppressed immune responses often found in nephrotic syndrome.


Plate fixation of prostheses after segmental resection for bone tumours.
This study investigated the concept of using plates to attach endoprostheses to bone after segmental resection for bone tumours in an animal model. Titanium alloy plates integrated with the prosthesis and coated with hydroxyapatite were attached to bone by screws. This type of uncemented fixation relied on the induction of periosteal bone formation into and around the plates to secure the implant to bone. Two, three, and six-slotted plate designs were investigated. On retrieval, each plate was securely fixed by new bone. Bone apposition on the external surface of the plates occurred through a combination of periosteal bone production, invasion of bone through slots in the plate, and bone growth over the ends of the plates. Most plates became incorporated into a remodelled cortex. Higher bone turnover rates (microm day(-1)) were seen in bone in the slots of the plate compared with normal cortical bone turnover (p < 0.05). Significantly higher rates of turnover were measured beneath slotted parts of the plates compared with regions below the unslotted parts (p < 0.05). The cross-sectional area of bone surrounding the six-plate implant design was significantly higher than that of the three-plate (p < 0.05) and two-plate (p < 0.05) designs. In addition, significantly more bone formed adjacent to the six-plated implant design compared with that in the contralateral limb (p = 0.002). However, no significant difference was found when the total cortical area around the three-plated design was compared with that of the contralateral limb (p = 0.63). In contrast, significantly less bone was measured adjacent to the two-plate design than in the untreated limb (p = 0.001). Image analysis also demonstrated increased cortical porosity adjacent to the six-plate design compared with the three-plate (p = 0.004) and two-plate (p < 0.05) designs. Finite element analysis demonstrated that the six and three-plate designs increased the second moment of area compared with that in the left tibia (p = 0.003 and 0.066, respectively). However, the attachment of the more flexible two-plate design did not significantly increase the second moment of area compared with that in the contralateral limb (p = 0.235). It was concluded that due to both mechanical and biological effects, the hydroxyapatite-coated plate designs generated new bone that enhanced fixation and encouraged plate integration into the load-bearing structure of the cortex. This method of fixation may be an alternative to the use of intramedullary cemented stems in patients requiring bone tumour implants and may be the only way to preserve the joint in difficult cases where only short segments of bone remain.


Public access to clinical trials: Lessons from an organizational implementation of policy.
Efforts to make clinical trials and their results more publicly available have been increasing in recent years. However, there is a need to better understand ways to achieve these goals aimed at benefiting a diverse set of stakeholders. Since 2005, the U.S. Department of Veterans Affairs Office of Research and Development (ORD), part of the nation's largest integrated health care system, has required the clinical trials its funds to be registered in ClinicalTrials.gov as a condition of the award. Furthermore, summary results of studies active since 2007 have been included in the registry. This paper highlights ORD activities, challenges and lessons at investigator, study, and organizational levels. Key factors in ORD's approach include: a mission-oriented approach; leadership support; a working group for organizational policies and practices; prioritizing communication; and recognizing the needs of investigators. Making clinical trials available to the public should represent a focal point for groups desiring to maximize the contributions from such research. The ability to do so must involve a commitment by sponsors and a critical evaluation of the reasons, requirements and resources at multiple levels.


Thoughts and Experiences of Behçet Disease From Participants on a Reddit Subforum: Qualitative Online Community Analysis.
Behçet disease (BD) is a type of vasculitis with relapsing episodes and multisystemic clinical features, associated with significant morbidity and impact on patients' lives. People affected by BD often participate in discussions of their illness experiences. In-person support groups have limited physical accessibility and a relative lack of anonymity; however, online communities have become increasingly popular. This study investigates the perspectives and experiences of people affected by BD by examining the content shared and discussed on a subforum of the website Reddit-a popular online space for anonymous discussions. All discussion threads posted between March 9, 2021, and March 12, 2022, including posts and comments, were examined from the subforum "r/Behcets," an anonymous online community of 1100 members as of March 2022. A Grounded Theory analysis was completed to identify themes and subthemes, and notable quotes were extracted from the threads. Parameters extracted from each post included the number of comments, net upvotes, category, and subcategories. Two research team members read the posts separately to identify initial codes and themes to ensure data saturation was achieved. Six recurring themes were identified: (1) finding connectedness and perspectives through shared experiences, (2) struggles of the diagnostic odyssey, (3) sharing or inquiring about symptoms, (4) expressing strong emotions relating to the experience of BD, (5) the impact of BD on quality of life and personal relationships, as well as (6) COVID-19 and the COVID-19 vaccination in relation to BD. Subthemes within each theme were also identified and explored. This novel study provides a qualitative exploration of the perspectives and experiences of people affected by BD, shared in the anonymous and accessible online community of Reddit. The study found that people impacted by an illness seek to connect and receive validation through shared conditions and experiences. By examining the content shared in r/Behcets, this study highlights the needs of people affected by BD, identifying gaps and areas for improvement in the in-person support they receive.


Bodily distalization of molars with absolute anchorage.
Palatal implants have been used over the last two decades to eliminate headgear wear and to establish stationary anchorage. In this case report, the stability of a palatal implant for distalization of molars bodily and for anchorage maintenance was assessed. The implant was a stepped screw titanium (4.5 mm diameter x 8 mm length), and it was placed in the palatal region for orthodontic purposes. A surgical template containing a metal drill housing was prepared. Angulation of the drill housing was controlled according to the radiologic tracing of the maxilla transferred to a plaster cast section in the paramedian plane. The implant was placed using a noninvasive technique (incision, flap, and suture elimination) and left transmucosally to facilitate the surgical procedure and to reduce the number of operations. The paramedian region was selected (1) to avoid the connective tissues of the palatine suture and (2) because it is considered to be a suitable host site for implant placement. After three months of healing, the implant was osseointegrated and orthodontic treatment was initiated. For molar distalization, the Keles Slider appliance was modified and, instead of a Nance button, a palatal implant was used for anchorage. The results showed that the molars were distalized bodily at five months, and no anchorage loss was observed. At the end of the treatment, the smile was improved, and an ideal Class I molar and canine relationship, an ideal overbite, and an ideal overjet were all achieved. In conclusion, palatal implants can be used effectively for anchorage maintenance and in space-gaining procedures. Use of a three-dimensional surgical template eliminated implant placement errors, reduced chair time, minimized trauma to the tissues, and enhanced osseointegration. This method can be used effectively to achieve distalization of molars bodily without anchorage loss.


APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry.
Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.


MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer.
Cancer cells display novel phosphopeptides in association with MHC class I and II molecules. In this study, we evaluated two HLA-A2-restricted phosphopeptides derived from the insulin receptor substrate (IRS)-2 and the cell-cycle regulator CDC25b. These proteins are both broadly expressed in multiple malignancies and linked to cancer cell survival. Two phosphopeptides, termed pIRS-21097-1105 and pCDC25b38-46, served as targets of strong and specific CD8 T-cell memory responses in normal human donors. We cloned T-cell receptor (TCR) cDNAs from murine CD8 T-cell lines specific for either pIRS-21097-1105 or pCDC25b38-46. Expression of these TCRs in human CD8 T cells imparted high-avidity phosphopeptide-specific recognition and cytotoxic and cytokine-secreting effector activities. Using these cells, we found that endogenously processed pIRS-21097-1105 was presented on HLA-A2(+) melanomas and breast, ovarian, and colorectal carcinomas. Presentation was correlated with the level of the Ser(1100)-phosphorylated IRS-2 protein in metastatic melanoma tissues. The highest expression of this protein was evident on dividing malignant cells. Presentation of endogenously processed pCDC25b38-46 was narrower, but still evident on HLA-A2(+) melanoma, breast carcinoma, and lymphoblastoid cells. Notably, pIRS-21097-1105-specific and pCDC25b38-46-specific TCR-expressing human CD8 T cells markedly slowed tumor outgrowth in vivo. Our results define two new antigens that may be developed as immunotherapeutic agents for a broad range of HLA-A2(+) cancers.


Prognostic Value of the Malnutrition-inflammation Score in Hospitalization and Mortality on Long-term Hemodialysis.
Since its development, cumulative evidence has accumulated regarding the prognostic value of the Malnutrition-Inflammation Score (MIS/Kalantar score) prognostic value; however, there is a shortage of recent and large studies with comprehensive statistical methodologies that contribute to support a higher level of evidence and a consensual cutoff. The aim of this study was to assess the strength of MIS association with hospitalization and mortality in a nationwide cohort. This was a historical cohort study of hemodialysis patients from 25 outpatient centers followed up for 48 months. Univariable and multivariable Cox additive regression models were used to analyze the data. The C-index was estimated to assess the performance of the final model. Two thousand four hundred forty-four patients were analyzed, 59.0% males, 32.0% diabetic, and median age of 71 years (P25 = 60, P75 = 79). During a median period of 45-month follow-up, with a maximum of 48 months (P25 = 31; P75 = 48), 875 patients presented an MIS <5 (35.8%) and 860 patients (35.2%) died. The proportion of deaths was 23.1% for patients with the MIS <5 and 41.9% if the MIS ≥5 (P < .001). A total of 1,528 patients (62.5%) were hospitalized with a median time to the first hospitalization of 26 months (P25 = 9; P75 = 45). A new cutoff point regarding the risk of death, MIS ≥6, was identified for this study data set. In multivariable analysis for hospitalization risk, a higher MIS, higher comorbidity index, and arteriovenous graft or catheter increased the risk, whereas higher Kt/V and higher albumin had a protective effect. In multivariable analysis for mortality risk, adjusting for age, albumin, normalized protein catabolic rate, Charlson comorbidity index, interdialytic weight gain, Kt/V, diabetes, hematocrit, and vascular access, patients with the MIS ≥6 showed a hazard ratio of 1.469 (95% confidence interval: 1.262-1.711; P < .001). Higher age, higher interdialytic weight gain, higher comorbidity index, and catheter increased significantly the risk, whereas higher Kt/V, higher albumin, and higher normalized protein catabolic rate (≥1.05 g/kg/d) reduced the risk. The MIS maintains its relevant and significant association with hospitalization and mortality.


Intestinal lymphangiectasia with protein-losing enteropathy in Waldenstrom macroglobulinemia.
Gastrointestinal complications of Waldenstrom macroglobulinemia (WM) are unusual but often treatable. We report a case of WM associated with significant gastrointestinal involvement manifest as chronic diarrhea with protein-losing enteropathy and recurrent venous thromboses. Small bowel biopsy was negative for amyloidosis but revealed intestinal lymphangiectasia with deposition of monoclonal IgM. The patient was treated with cyclophosphamide, vincristine, and prednisone with rapid and complete resolution of the peripheral edema and diarrhea. We follow the case report with a retrospective analysis of patients with WM and gastrointestinal symptoms seen at our institution, and review the available literature on this unusual association. An increased awareness of the gastrointestinal manifestations of WM may help to explain and to treat the chronic, debilitating, and potentially life-threatening symptoms in patients with this lymphoproliferative disorder.


Severity of angiographically proven coronary artery disease predicts smoking cessation.
We investigated the relationship between the extent of coronary artery disease (CAD) and the likelihood of cigarette smoking cessation in a population of 84 smokers between 21 and 75 years of age undergoing elective or urgent coronary angiography at the University of Massachusetts Medical Center. The smokers were enrolled in a pilot study investigating the relationship of hospitalization and coronary arteriography for coronary artery disease to subsequent smoking cessation and were scored at baseline as having none, one-, two-, or three-vessel disease. Smoking status at a mean follow-up time of 11 months was obtained by telephone interview, at which point 50% reported not smoking. Logistic regression showed a significant relationship between smoking cessation and two factors: the anatomic extent of CAD and the experience of having had coronary artery bypass surgery or percutaneous transluminal coronary angioplasty following the initial catheterization. We discuss the relative roles of patient knowledge and motivation and physician intervention, and their implications for smoking cessation interventions.


Maternal conception of gestational weight gain among Latinas: A qualitative study.
Interventions to support healthy gestational weight gain are often ineffective. The objective was to develop a model of how pregnant Latinas-who have a higher risk of poor maternal and neonatal weight-related outcomes-conceptualize healthy gestational weight gain, providing guidance for future interventions. Ten focus groups with 50 pregnant Latinas were conducted by a native Spanish-speaking female moderator. On the basis of participant responses, we used grounded theory to inductively develop a personal conceptual framework for gestational weight gain. Commonly identified barriers to being active and healthy eating included negative emotions, body image, physical discomfort, low energy, and lack of motivation. Women identified sociocultural issues such as a sense of isolation from family (among immigrants) and the degree of perceived social support as important contributors to health behaviors. Two personal health schemas emerged from participant responses. The "mother-child health schema" describes the degree to which participants recognized the interrelatedness of health needs for baby and for themselves. The "attention to gestational weight gain schema" describes how a respondent's attention to and perceived importance of gestational weight gain influences health-related behaviors during pregnancy. Women's sociocultural and interpersonal context influence weight-related behaviors through the lens of personal health schemas. Understanding how cognitive aspects relate to traditional behavioral determinants suggests several opportunities for intervention, such as focusing on healthy behaviors instead of numerical targets for healthy weight gain. Although derived from Spanish-speaking Latin-American women, these results may also be potential leverage points for other minority groups. (PsycINFO Database Record


Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis.
Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA). We investigated the in vitro effects of IL-27, alone or in combination with inflammatory cytokine tumor necrosis factor (TNF)-α or IL-1 β on the pro-inflammatory activation of human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects, and the underlying intracellular signaling molecules were determined by intracellular staining using flow cytometry. Significantly higher plasma concentration of IL-27 was found in RA patients (n = 112) than control subjects (n = 46). Both control and RA-FLS constitutively express functional IL-27 receptor heterodimer, gp130 and WSX-1, with more potent IL-27-mediated activation of signal transducers and activators of transcription (STAT)1 in RA-FLS. IL-27 was found to induce significantly higher cell surface expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and release of inflammatory chemokine IL-6, CCL2, CXCL9, CXCL10 and matrix metalloproteinase-1 of RA-FLS than that of control FLS (all P < 0.05). Moreover, an additive or synergistic effect was observed in the combined treatment of IL-27 and TNF-α or IL-1 β on the surface expression of ICAM-1 and VCAM-1 and the release of CXCL9 and CXCL10 of RA-FLS. Further investigations showed that the expression of ICAM-1, VCAM-1 and chemokines stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, c-Jun amino-terminal kinase and Janus kinase pathways. Our results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.


Changes in miR-143 and miR-21 expression and clinicopathological correlations in pancreatic cancers.
Despite advances in clinical management of pancreatic cancer (PC), there is still room for improvement in early detection, diagnosis, and treatment strategies. The role of microRNAs (miRNAs) in tumor biology might pinpoint an alteration in expression of miRNAs as new diagnostic/prognostic biomarkers. Expression levels of miR-143 and miR-21 and correlations with clinicopathological features were analyzed in 26 matched pairs of tumor and adjacent noncancerous tissue samples collected from patients with PCs, including 18 pancreatic ductal adenocarcinomas (PDACs) and 8 adenocarcinomas of Vater's papilla (PVACs). Compared to normal tissues, miR-143 was up-regulated in both PDAC and PVAC tumor samples (P = 0.0028 and P = 0.039, respectively). Conversely, alterations in miR-21 expression were significantly different in PDAC versus PVAC samples (P = 0.0049). Tumor levels of miR-21 were associated with preoperative serum levels of CA 19-9 (r = 0.63, P = 0.0022), whereas miR-143 expression was negatively correlated to lymph node spreading (r = -0.64; P = 0.0004). Correlation between miR-143 and miR-21 expression levels in patients with PDAC was observed (r = 0.53, P = 0.023). Deregulation of miR-143 and miR-21 may reflect histological features and biological behavior of different PCs. Association data with clinical parameters might indicate a prognostic significance for miR-143 and miR-21 in PCs.


Nitric oxide decreases insulin resistance induced by high-fructose feeding.
The effect of nitric oxide (NO) on insulin resistance was studied in high-fructose-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure was employed (insulin infusion rates: 3 and 30 mU/kg BW/min) in 12 high-fructose-fed rats and 12 chow-fed rats while awake. Half of the high-fructose-fed and the chow-fed rats, respectively, were continuously given sodium nitroprusside (SNP, 3 ng/kg BW/min) during the clamp study. Blood glucose was clamped at the fasting level in each rat. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Metabolic clearance rate of glucose (MCR) was regarded as an index of whole body insulin action. At both 3 and 30 mU/kg BW/min insulin infusions, high-fructose feeding showed a significant decrease in MCR compared with the chow-fed rats. However, decreased MCRs were stimulated by SNP administration and reached similar levels as the chow-fed rats. SNP infusion did not influence MCRs in the chow-fed rats. Therefore it could be concluded that NO can improve insulin resistance induced by high-fructose feeding.