Real-World 1-Year Retention Rate of Subcutaneous Tocilizumab Treatment in Patients with Moderate to Severe Active Rheumatoid Arthritis: TANDEM Study.
Drug retention is particularly relevant to assess long-term treatments. This real-world study mainly aimed to describe 1-year retention rate (RR) of subcutaneously administered tocilizumab (TCZ-SC) in patients with moderate to severe active rheumatoid arthritis (RA). This non-interventional, prospective, multicenter study (NCT02608112) was conducted in patients with RA initiating TCZ-SC treatment, with an 18-month follow-up. RR was estimated at month 12 in the overall population and baseline subgroups (combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) or not, age, body mass index, methotrexate dose), using the Kaplan-Meier method. Patient compliance to TCZ-SC was described using the 5-item Compliance Questionnaire for Rheumatology (CQR5). At inclusion 75% of the 285 analyzed patients were women, mean RA duration was 9 ± 9 years, previous RA treatments included biological agents (63%) and/or csDMARDs (94%), mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 4.8 ± 1.2. TCZ-SC RR at month 12 was estimated to be 64% (95% CI 58%-69%) with no statistical differences between subgroups. Clinical results improved with TCZ-SC; the proportion of patients treated with combined glucocorticoids decreased from 49% to 22% at month 12. At each follow-up time, at least 80% of patients were high adherers to TCZ-SC (at least 80% of theoretical injections). Among the 286 patients with at least one TCZ-SC injection, 25 patients (9%) experienced serious adverse events related to TCZ-SC with no differences according to patient age. This real-world study corroborates the RR at month 12 previously shown in interventional studies on TCZ-SC. Our data suggest there are no differences according to patient's profile (age, BMI), methotrexate doses, and TCZ-SC use. NCT02608112.


BrdU-Hoechst-Giemsa analysis of DNA replication in synchronized lymphocyte cultures. Study of human X and Y chromosomes.
The combination of a technique of reversible methotrexate (MTX) imposed G1/S block in cultures of human lymphocytes with the BrdU-Hoechst-Giemsa technique permitted the study of DNA replication patterns in individual chromosomes at different intervals of the S phase in a cell cohort with uniform S + G2 duration. The procedure did not increase either the frequency of chromosomal breakage or SCE frequency. The technique applied permitted visualization of the banding pattern in over 90% of mitoses. Examination of mitosis following different times of exposure to BrdU revealed a high degree of synchrony in the progression of the cell cohort examined through the S phase. The presence of two distinct late replication patterns of the allocyclic X chromosome was confirmed in studies on lymphocytes from normal human females by this technique. Interindividual and intercellular differences of the replication pattern have been demonstrated. The replicating patterns from one individual were relatively constant. The analysis of the Y chromosome has revealed marked differences of the termination of replication in individual cells. Euchromatic regions have been shown to complete DNA synthesis first, followed by the distal part of the long arm and, finally, by the region of Yq11/Yq12 junction. Lateral asymmetry was localised at this region.


Phosphate starvation promoted the accumulation of phenolic acids by inducing the key enzyme genes in Salvia miltiorrhiza hairy roots.
Phosphate starvation increased the production of phenolic acids by inducing the key enzyme genes in a positive feedback pathway in Saliva miltiorrhiza hairy roots. SPX may be involved in this process. Salvia miltiorrhiza is a wildly popular traditional Chinese medicine used for the treatment of coronary heart diseases and inflammation. Phosphate is an essential plant macronutrient that is often deficient, thereby limiting crop yield. In this study, we investigated the effects of phosphate concentration on the biomass and accumulation of phenolic acid in S. miltiorrhiza. Results show that 0.124 mM phosphate was favorable for plant growth. Moreover, 0.0124 mM phosphate was beneficial for the accumulation of phenolic acids, wherein the contents of danshensu, caffeic acid, rosmarinic acid, and salvianolic acid B were, respectively, 2.33-, 1.02-, 1.68-, and 2.17-fold higher than that of the control. By contrast, 12.4 mM phosphate inhibited the accumulation of phenolic acids. The key enzyme genes in the phenolic acid biosynthesis pathway were investigated to elucidate the mechanism of phosphate starvation-induced increase of phenolic acids. The results suggest that phosphate starvation induced the gene expression from the downstream pathway to the upstream pathway, i.e., a feedback phenomenon. In addition, phosphate starvation response gene SPX (SYG1, Pho81, and XPR1) was promoted by phosphate deficiency (0.0124 mM). We inferred that SPX responded to phosphate starvation, which then affected the expression of later responsive key enzyme genes in phenolic acid biosynthesis, resulting in the accumulation of phenolic acids. Our findings provide a resource-saving and environmental protection strategy to increase the yield of active substance in herbal preparations. The relationship between SPX and key enzyme genes and the role they play in phenolic acid biosynthesis during phosphate deficiency need further studies.


Stromal cells as the major source for matrix metalloproteinase-2 in cutaneous melanoma.
Matrix metalloproteinases (MMPs) are essential for tumor progression, invasion and metastases formation. Expression of these proteinases is not only restricted to the tumor cells themselves, but also is found in normal stromal cells. Moreover, immunohistochemistry suggests stromal cells as the major source. To scrutinize this hypothesis we established a slowly growing, syngeneic tumor model using the B16-melanoma cell line B78D14. In vitro analysis demonstrated that B78D14 cells secreted MMP-2, MT1-MMP, and to a lesser degree MMP-9; in addition they expressed both MT1-MMP and EMMPRIN on their surface. In subcutaneous (s.c.) tumors of these cells MMP-2 expression was predominantly present at the tumor-stroma border indicating stromal cells as primary source for this protease in vivo. Indeed, double staining experiments and in situ zymography confirmed that tumor adjacent stromal cells at the invasive front expressed MMP-2 and only at this site activated MMP-2 was detectable. Notably, in an experimental pulmonary metastases model neither tumor nor stromal cells expressed MMP-2, suggesting that the capacity of stromal cells is largely dependent on the surrounding microenvironment.


Some determinants of affective symptoms in epileptics.
Forty-two epileptics were given a psychiatric interview and completed five questionnaires. Current affective symptoms were significantly associated with a past history of neurotic disorder but not with temporal lobe epilepsy.


Existing antilisterial immunity does not inhibit the development of a Listeria monocytogenes-specific primary cytotoxic T-lymphocyte response.
Infection of BALB/c mice with Listeria monocytogenes stimulates an antilisterial immune response evident by the appearance of H2-Kd-restricted CD8(+) cytotoxic T lymphocytes (CTLs) specific for the nanomer peptides amino acids (aa) 91 to 99 of listeriolysin O (LLO 91-99) and aa 217 to 225 of the p60 molecule (p60 217-225). We have introduced point mutations at anchor residues within LLO 91-99 (92F) or p60 217-225 (218F), and BALB/c mice infected with L. monocytogenes strains containing these point mutations do not develop CTLs specific for LLO 91-99 or p60 217-225, respectively. We have used these strains to test whether primary CTL responses against L. monocytogenes-derived determinants can be stimulated within an environment of existing antilisterial immunity. We found that the development of a primary L. monocytogenes-specific CTL response is not altered by existing immunity to L. monocytogenes. For example, primary immunization with the p60 218F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of p60 217-225-specific CTLs at primary response levels and LLO 91-99-specific effectors at levels consistent with a memory CTL response. Similarly, primary immunization with the 92F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of LLO 91-99-specific CTLs at primary response levels and p60 217-225-specific effectors at levels consistent with a memory CTL response. These results provide additional support for the use of L. monocytogenes as a recombinant vaccine vector and show that antivector immunity does not inhibit the development of a primary CTL response when the epitope is delivered by L. monocytogenes as the vaccine strain.


Effects of cilofungin (LY121019) on carbohydrate and sterol composition of Candida albicans.
Cilofungin (LY 121019) is a novel analogue of echinocandin B with potent activity against Candida albicans. The effects of cilofungin on the sterol and cell wall carbohydrate composition of Candida albicans were investigated. Exposure of Candida albicans to cilofungin resulted in a 55-60% decrease in ergosterol and a 4-13% decrease in lanosterol content relative to controls. Carbohydrate analysis revealed a 72-79% decrease in glucan content and no significant decrease in mannan or chitin content relative to controls. These studies suggest that cilofungin specifically inhibits glucan synthesis in Candida albicans and thus may be less toxic to mammalian cells. The effects of cilofungin on sterol composition may be non-specific and will require additional investigation.


Partial purification and characterization of an ovarian tripeptidyl peptidase: a lysosomal exopeptidase that sequentially releases collagen-related (Gly-Pro-X) triplets.
The pregnant hog ovary is a rich source of a novel exopeptidase that catalyzes the release, at pH 5.0, of collagen-related (P3-P2-P1) "triplets" such as Gly-Pro-Met, Gly-Pro-Arg, and Gly-Pro-Ala from arylamide derivatives, provided the N termini are unsubstituted. Corresponding derivatives of related (P2-P1) dipeptides (Pro-Met, Pro-Ala) or (P1) amino acids (Met, Arg, Ala) are not attacked. The enzyme was purified 58-fold from a detergent extract of a water-extracted tissue residue. Activity was determined on Gly-Pro-Met-2-naphthylamide at pH 4.5 and 37 degrees C (Km 0.45 mM; Vmax 722 nmoles/min/mg protein). The responsible Mr 55,000 exopeptidase, termed "tripeptidyl peptidase", forms high-Mr aggregates, belongs to the serine catalytic class, and has a lysosomal localization. Gly-Pro-Ala triplets were released sequentially at pH 5.0 from a Mr 14,000 polypeptide, poly(Gly-Pro-Ala-). When this reaction was coupled to that of homologous dipeptidyl peptidase II, the liberated tripeptides were reduced to dipeptides and free amino acids: (Gly-Pro-Ala)n----nGly-Pro-Ala----nGly-Pro + nAla.


Ferrocene-derived pyrazinoyl and nicotinoyl schiff-bases: their synthesis, characterization and biological properties.
A novel class of acetylferrocene-derived Schiff-bases such as 2-pyrazinoyl-1-(2-ferroceneylmethylene)- hydrazide (HL(1)) and 2-nicotinoyl-1-(2-ferrocenylmethylene)hydrazide (HL(2)) have been synthesized and characterized by their IR, (1)H NMR, (13)C NMR and microanalytical date. The biological effect induced due to the coupling of ferrocene molecule with the aroylhydrazines e.g., pyrazinoylhydrazine and nicotinoylhydrazine has been studied against bacterial species such as Escherichia coli, Pseudomonas aeruginosa , Staphylococcus aureus and Klebsiella pneumonae.


New insight into comprehensive analysis of INDETERMINATE DOMAIN (IDD) gene family in rice.
The INDETERMINATE DOMAIN (IDD) transcription factor (TF), as a family of plant-specific zinc-finger proteins, regulates a variety of development processes and abiotic stresses in plants. IDD genes have been identified and characterized in other plants, however, the rice IDD family genes have not been investigated at genome-wide. In this study, 15 OsIDD genes were identified in rice genome and phylogenetically classified into two groups. Conserved motifs and potential interaction protein analysis about OsIDD proteins were carried out. Exon-intron structures, cis-acting elements and expression profiles of OsIDD genes were also examined. Exon-intron structures analysis revealed that overall structures of OsIDD genes were relatively conserved although they contained different numbers of introns. Cis-acting elements analysis suggested that most OsIDD gene transcripts could be induced by various abiotic stresses and phytohormones. The expression patterns of OsIDD genes were detected by qRT-PCR under cold and drought conditions, and by exogenous auxin (2,4-D), gibberellin (GA3), and abscisic acid (ABA) treatments, respectively. The results showed that the OsIDDs might play essential roles under abiotic stresses and hormone responses. Distinct expression profiles in tissues/organs suggested that OsIDDs might be involved in different development processes in rice. More interestingly, the prediction of protein-protein interactions (PPIs) revealed OsIDDs could cooperate with some histone modifiers. Yeast two-hybrid assays were performed and confirmed it. Collectively, these results provide a foundation for further elucidation on the molecular mechanisms of OsIDD genes and advance our understanding of their biological function in rice.


Characterization of nitrogen and phosphorus at the ice-water-sediment interface and the effect of their migration on overlying water quality in Daihai Lake (China) during the freezing period.
Approximately one-third of the year, Daihai Lake experiences freezing conditions. During this period, the primary mechanisms that impact the quality of the lake water quality include the freezing of nutrients by the ice sheet and the migration of nutrients between the ice, water, and sediment. The present investigation involved the collection of samples of ice, water, and sediment, followed by the utilization of the thin film gradient diffusion (DGT) technique to and explore the distribution and migration of diverse nitrogen (N) and phosphorus (P) forms at the interface of ice, water and sediment. The findings indicate that the freezing process led to the precipitation of ice crystals, which in turn caused the migration of a significant proportion (28-64 %) of nutrients to the subglacial water. The predominant constituents of N and P in subglacial water, were NO3--N and PO43--P, which constituted 62.5-72.5 % of total N (TN) and 53.7-69.4 % of total P(TP). Respectively, with increasing depth, the TN and TP of sediment interstitial water increased. The sediment in the lake acted as a source of PO43--P and NO3--N while acting as a sink or NH4+-N. Soluble reactive P (SRP) flux and NO3--N flux were responsible for 76.5 % and 2.5 % of the P and N present in the overlying water. Additionally, it was observed that 60.5 % of the NH4+-N flux in the overlying water was absorbed and subsequently deposited in the sediment. The presence of soluble and active P in the ice sheet could play a crucial role in the regulation of sediment release of both SRP and NH4+-N. Additionally, the presence of high nutritional salts and the concentration of nitrate nitrogen in the overlying water would certainly increase the pressure of the water environment. Endogenous contamination must be urgently controlled.


The human PGM-2 and its chromosomal localization in man-mouse hybrids.
A detailed procedure is described for a rapid detection of phosphoglucomutase-2(=phosphopentomutase;PGM-2) on Cellogel following electrophoresis of extracts of human red blood cells and other tissues, including cultured fibroblasts and various types of primate-rodent somatic hybrid cells. The present study indicated that there is only one locus for phosphopentomutase in man. The data from a selected panel of 20 independent clones of man-mouse somatic cell hybrids, investigated for the presence of human chromosomes and for the presence or absence of human PGM-2 favored the assignment of the human PGM-2 locus to chromosome 4.


Prognostic value of tumor cavitation in extensive-stage small-cell lung cancer patients treated with anlotinib.
Anlotinib is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. The efficacy of anlotinib as a third-line or beyond therapy for SCLC was confirmed in the ALTER1202 trial. For lung cancer patients treated with antiangiogenesis agents, the phenomenon of cavitation is commonly seen in the lung target lesions. The impact of tumor cavitation on survival in lung cancer patients treated with vascular-targeted therapy remains controversial. Our retrospective study was to investigate the prognostic value of tumor cavitation in extensive-stage SCLC patients treated with anlotinib. A total of 73 extensive-stage SCLC patients confirmed by histopathology from January 2018 to January 2019 were retrospectively analyzed. All patients received anlotinib therapy at Shanghai Chest Hospital. We defined tumor cavitation of the lung target lesions as that part of solid component was changed to air-filled area according to chest CT. Progression-free survival (PFS) was calculated from the beginning of anlotinib therapy to the disease progression or the last follow-up visit. Eleven (15.0%) patients had tumor cavitation during anlotinib therapy. The ORR of the 73 patients was 15.1%. Multivariate logistic regression analysis showed that tumor cavitation during anlotinib therapy was not associated with gender (P = 0.630), age (P = 0.190), smoking status (P = 0.165), anatomy type (P = 0.641), and the line of anlotinib therapy (P = 0.302). The median PFS of all patients was 2.6 months (95%CI 2.1-3.2). According to the univariate analysis, the median PFS in patients with and without tumor cavitation was 5.0 months and 2.2 months, respectively, and the difference was statistically significant (P = 0.041). According to the multivariate analysis, tumor cavitation was an independent factor for PFS after adjusting gender, age, smoking status, anatomy type, the line of anlotinib therapy, tumor cavitation, and response to anlotinib (adjusted HR 0.316, 95%CI 0.142-0.702; P = 0.005). In 73 extensive-stage SCLC patients treated with anlotinib, no demographic/clinical characteristic was related to tumor cavitation, and tumor cavitation was an independent factor in predicting better PFS.


Benefits of robotically-assisted surgery for complex mitral valve repair.
To determine whether robotic mitral valve repair can be applied to more complex lesions compared with minimally invasive direct mitral valve repair through a right thoracotomy. We enrolled 335 patients over a 9-year period; 95% of the robotic surgeries were performed after experience performing direct mitral valve repair. The mean age in the robotic versus thoracotomy repair groups was 61 ± 14 vs 55 ± 11 years, respectively (P < 0.001); 97% vs 100% of the patients, respectively, had degenerative aetiologies. Repair complexity was simple in 106 (63%) vs 140 (84%), complex in 34 (20%) vs 20 (12%) and most complex in 29 (17%) vs 6 (4%) patients undergoing robotic versus thoracotomy repair, respectively. The average complexity score with robotic repair was significantly higher versus thoracotomy repair (P < 0.001). The robotic group underwent more chordal replacement using polytetrafluoroethylene and less resections. All patients underwent ring annuloplasty. Cross-clamp time did not differ between the groups, and no strokes or deaths occurred. More patients undergoing robotic repair underwent concomitant procedures versus the thoracotomy group (30% vs 14%, respectively; P < 0.001). The overall repair rate was 100%, with no early mortality or strokes in either group. Postoperative mean residual mitral regurgitation was 0.3 in both groups, and the mean pressure gradient through the mitral valve was 2.4 vs 2.7 mmHg (robotic versus thoracotomy repair, respectively; P = 0.031). Robotic surgery can be applied to repair more complex mitral lesions, with excellent early outcomes.


Corrosion behavior of biomedical Ti-24Nb-4Zr-8Sn alloy in different simulated body solutions.
Corrosion behavior of a multifunctional biomedical titanium alloy Ti-24Nb-4Zr-8Sn (wt.%) in 0.9% NaCl, Hank's solution and artificial saliva at 37 °C was investigated using open circuit potential, impedance spectroscopy and potentiodynamic polarization techniques, and some results were compared with pure titanium and Ti-6Al-4V alloy. The results showed that the alloy exhibited good corrosion resistance due to the formation of a protective passive film consisting mainly of TiO2 and Nb2O5, and a little of ZrO2 and SnO2. Ca ions were detected in the passive film as the alloy immersed in Hank's and artificial saliva solutions and they have negative effect on corrosion resistance. The EIS results indicated that either a duplex film with an inner barrier layer and an outer porous layer or a single passive layer was formed on the surface, and they all transformed into stable bilayer structure as the immersion time increased up to 24h. The polarization curves demonstrated that the alloy had a wider passive region than pure titanium and Ti-6Al-4V alloy and its corrosion current density (less than 0.1 μA/cm(2)) is comparable to that of pure titanium.


CT findings after pelvic exenteration: review of normal appearances and most common complications.
The aim of this review is to illustrate normal computed tomography (CT) findings and the most common complications in patients who underwent pelvic exenteration (PE) for advanced, persistent or recurrent gynecological cancers. We review the various surgical techniques used in PE, discuss optimal CT protocols for postsurgical evaluation and describe cross-sectional imaging appearances of normal postoperative anatomic changes as well as early and late complications. The interpretation of abdominopelvic CT imaging after PE is very challenging due to remarkable modifications of normal anatomy. After this radical pelvic surgery, the familiarity with expected CT appearances is crucial for diagnosis and appropriate management of potentially life-threatening complications in patients who underwent PE.


Effect of the Concomitant Use of Subcutaneous Basal Insulin and Intravenous Insulin Infusion in the Treatment of Severe Hyperglycemic Patients.
No consensus exists regarding the early use of subcutaneous (SC) basal insulin facilitating the transition from continuous intravenous insulin infusion (CIII) to multiple SC insulin injections in patients with severe hyperglycemia other than diabetic ketoacidosis. This study evaluated the effect of early co-administration of SC basal insulin with CIII on glucose control in patients with severe hyperglycemia. Patients who received CIII for the management of severe hyperglycemia were divided into two groups: the early basal insulin group (n=86) if they received the first SC basal insulin 0.25 U/kg body weight within 24 hours of CIII initiation and ≥4 hours before discontinuation, and the delayed basal insulin group (n=79) if they were not classified as the early basal insulin group. Rebound hyperglycemia was defined as blood glucose level of >250 mg/dL in 24 hours following CIII discontinuation. Propensity score matching (PSM) methods were additionally employed for adjusting the confounding factors (n=108). The rebound hyperglycemia incidence was significantly lower in the early basal insulin group than in the delayed basal insulin group (54.7% vs. 86.1%), despite using PSM methods (51.9%, 85.2%). The length of hospital stay was shorter in the early basal insulin group than in the delayed basal insulin group (8.5 days vs. 9.6 days, P=0.027). The hypoglycemia incidence did not differ between the groups. Early co-administration of basal insulin with CIII prevents rebound hyperglycemia and shorten hospital stay without increasing the hypoglycemic events in patients with severe hyperglycemia.


Effects of tobacco smoking and age on the keratinization of palatal mucosa: a cytologic study.
Cytologic smears of palatal mucosa were evaluated for degree of keratinization in 217 healthy men ranging in age from 30 to 74 years. Two slides were prepared for each participant, and each slide was read by two different pathologists. Three separate high-power fields were examined on each slide, and the percentage of orange-brown cells, either without nuclei or with pyknotic or fragmented nuclei, was recorded. A mean value was obtained for each participant. Each participant had an extensive medical and dental work-up as part of the Veterans Administration Longitudinal Study of Oral Health in Healthy Veterans. Nonsmokers and smokers were divided into five age groups. Smokers at all ages presented a greater degree of palatal keratinization than nonsmokers, but age differences in keratinization were not statistically significant.


The role of peer review in a health care organization driven by TQM/CQI.
Many health care organizations have embraced the philosophy and tools of total quality management (TQM) and continuous quality improvement (CQI) without overt linkage to existing peer review processes. Achieving total quality in an organization requires that both peer review and TQM/CQI improvement processes be effectively used. Three ways of linking peer review and TQM/CQI include: 1) coordinating TQM/CQI and peer review quality improvement initiatives whenever possible; 2) expanding the focus of peer review to include assessment of the processes and systems within which the clinician functions; and 3) linking peer review and TQM/CQI improvement processes to address behavioral and attitudinal issues having economic roots.


Isolation of di-N-2-propylpentyl phthalate from human urine.
A higher percentage of di-N-2 propylpentyl phthalate isolated from the urine of the normals and a lower quantity in the patients suffering from Eales' disease accompanied with the occurrence in patients of another compound which is also most likely a phthalate ester has been correlated with the Eales' disease.


Osseointegration: the slow delivery of BMP-2 enhances osteoinductivity.
Although the placement of dental and orthopedic implants is now generally a safe, reliable and successful undertaking, the functional outcome is less assured in patients whose bone-healing capacity is compromised. To enhance peri-implant osteogenesis in these individuals, BMP-2 could be locally administered. However, neither a free suspension nor an implant-adsorbed depot of the agent is capable of triggering sustained bone formation. We hypothesize that this end could be achieved by incorporating BMP-2 into the three-dimensional crystalline latticework of a bone-mineral like, calcium-phosphate implant coating, where from it would be liberated gradually - as the inorganic layer undergoes osteoclast-mediated degradation - not rapidly, as from an implant-adsorbed (two-dimensional) depot. To test this postulate, we compared the osteoinductive efficacies of implant coatings bearing either an incorporated, an adorbed, or an incorporated and an adsorbed depot of BMP-2 at a maxillary site in miniature pigs. The implants were retrieved 1, 2 and 3 weeks after surgery for the histomorphometric analysis of bone formation within a defined 'osteoinductive' space. At each juncture, the volume of newly-formed bone within the osteoinductive space was greatest around implants that bore a coating-incorporated depot of BMP-2, peak osteogenic activity being attained during the first week and sustained thereafter. In the other groups, the temporal course of bone formation was variable, and the peak levels were not sustained. The findings of this study confirm our hypothesis: they demonstrate that we now have at our disposal a means of efficaciously augmenting and expediting peri-implant bone formation. Clinically, this possibility would render the process of implant placement a safer and a more reliable undertaking in patients whose bone-healing capacity is compromised, and would also permit a curtailment of the postoperative recovery period by a forestallment of the mechanical-loading phase.


Research on the pathophysiology, treatment, and prevention of suicide: practical and ethical issues.
Despite decades of research, the rate of death from suicide is rising in the United States. Suicide is a complex and multifactorial phenomenon and, to date, no validated biomarkers that predict suicidal behavior have been identified. Only one FDA-approved drug to prevent suicide exists, and it is approved only for patients with schizophrenia. Although anti-suicide psychotherapeutic techniques exist, treatment takes time, and only preliminary data exist for rapid-acting therapies. While more research into suicidal ideation and acute suicidal behavior is clearly needed, this research is fraught with both practical and ethical concerns. As a result, many investigators and bioethicists have called for restrictions on the types of research that individuals with suicidal behavior can participate in, despite the fact that the available empirical evidence suggests that this research can be done safely. This manuscript presents background information on the phenomenology of suicide, discusses the current state of treatment and prevention strategies, and reviews the practical and ethical issues surrounding suicide research in the context of available empirical data. Currently, the causes of suicide are poorly understood, in part due to the fact that very few studies have investigated the acute suicidal crisis. Although some biomarkers for predicting risk have been developed, none have been sufficiently validated. The most successful current interventions involve means restriction. However, while numerous hurdles face researchers, these are not insurmountable. The available evidence suggests that research into suicide can be conducted both safely and ethically.


Air pollution particulate matter (PM2.5)-induced gene expression of volatile organic compound and/or polycyclic aromatic hydrocarbon-metabolizing enzymes in an in vitro coculture lung model.
The overarching goals were: (i) to develop an in vitro coculture model, including two relevant lung target cells: human alveolar macrophage (AM) isolated from bronchoalveolar lavage fluid, and immortalized cells originated from the normal lung tissue of a human embryo (L132 cell line), as a future strategy for near-realistic exposures to air pollution particulate matter (PM), and (ii) to study the gene expression of volatile organic compound (VOC) and/or polycyclic aromatic hydrocarbons (PAH)-metabolizing enzymes in this in vitro coculture model. Human AM and/or L132 cells in mono- and coculture were exposed for 24, 48 and 72h to Dunkerque City's PM2.5 at its lethal concentrations at 10% and 50% (i.e. AM: LC10=14.93 microgPM/mL and LC50=74.63 microgPM/mL; L132: LC10=18.84 microgPM/mL and LC50=75.36 microgPM/mL), and the gene expression (i.e. Cytochrome P450 1A1, CYP1A1; CYP2E1; CYP2F1; microsomal Epoxide Hydrolase; NADPH Quinone Oxydo-Reductase-1, NQO1; and Glutathione S-Transferase pi-1 and mu-3, GST-pi1 and GST-mu3) was studied. In human AM in mono- and coculture, and in L132 cells in monoculture, VOC and/or PAH-coated onto PM induced the gene expression of CYP1A1, CYP2E1, NQO1, GST-pi1, and/or GST-mu3. However, there were quiet different outcomes based on the use of L132 cells in mono- vs. coculture: the pattern of VOC and/or PAH-metabolizing enzymes induced by PM in L132 cells in monoculture remained almost unaffected when in coculture with AM. Taken together, these results reinforced the key role of PM-exposed target human AM in the defenses of the human lung from external injuries, notably through their higher capacity to retain PM, and indicated that carbonaceous cores of PM, as physical vector of the penetration and retention of coated-VOC and/or PAH into cells, enabled them to exert a longer toxicity. The use of such a near realistic exposure system could also be a very useful and powerful tool to identify the mechanisms by which air pollution PM induced adverse health effects.


Subspecialty Breast Imaging Education in Tanzania; Clinical, Infrastructure, and Logistical Paradigms for Best Practices in the Low- and Middle-Income Settings.
We present subspecialty radiologist training for breast imaging at an Academic center in Dar Es Salaam, Tanzania. The training incorporates remote, in-person, asynchronous and synchronous teaching methods and multidisciplinary conferences. We use a team of US academic faculty under the auspices of the Radiological Society of North America Global Learning centers paradigm. Trainees are Tanzanian radiologists who are pursuing an additional specialization degree in Women's imaging, utilizing an approved 2-year curriculum. Challenges and opportunities in providing image-guided intervention and diagnosis training in the low- and middle-income settings are presented.


A strategy for the discovery and validation of toxicity quality marker of Chinese medicine based on network toxicology.
Considering that the quality control indicators in Chinese medicine (CM) are disconnected from safety and effectiveness, Prof. Chang-xiao Liu et al. has proposed a concept regarding the quality marker (Q-marker) of CM to promote the healthy development of the CM industry and improve the CM quality control method. In this study, we proposed a strategy to discover and verify the toxicity Q-marker of CM based on network toxicology. First, traditional biochemical pathology indicators and sensitive biomarkers were used to predict the toxicity of CM. Next, the chemical composition of toxic CMs and their metabolites were rapidly identified by multidimensional detection techniques. Subsequently, the interaction network between "toxicity - toxic chemical composition - toxic target - effect pathway" was built through network toxicology, and the potential toxicity Q-marker of CM was initially screened. Finally, the chemical properties of toxicity Q-markers were verified by traceability and testability. Based on the predicted results of network toxicology, the toxic compounds of CM were preliminarily identified, and the toxic mechanism was comprehensively interpreted. In the context of definite biological properties and chemical properties, the toxicity Q-marker was finally confirmed. This extensive review provides a study method for the toxicity Q-marker of CM, which helps to systemically and thoroughly reveal the internal toxicity mechanism of CM. The in-depth study of the toxicity Q-marker provides the material basis and technical support for the safety evaluation of CM.


Cancer Therapy-Related Cardiac Dysfunction in Patients Treated with a Combination of an Immune Checkpoint Inhibitor and Doxorubicin.
Backgrounds: There are scarce data on whether immune checkpoint inhibitors (ICIs) increase the risk of cardiac dysfunction when used with cardiotoxic agents. Thus, we evaluated cardiac dysfunction in patients with sarcoma receiving doxorubicin with or without ICI using echocardiography and left ventricular global longitudinal strain (LVGLS). Methods: A total of 95 patients were included in this study. Echocardiography and LVGLS were evaluated at baseline and follow-up (at 3 and 6 months of chemotherapy) and compared with the doxorubicin (Dox; n = 73) and concomitant ICI with doxorubicin (Dox-ICI; n = 22) groups. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a left ventricular ejection fraction (LVEF) drop of >10% and LVEF of <50% (definite CTRCD), LVEF drop of >10%, LVEF of ≥50%, and LVGLS relative reduction of >15% (probable CTRCD) at six months. Results: There were no significant differences in age, cumulative dose of doxorubicin, and cardiovascular risk factors between the two groups. At baseline, the LVEF was similar in the Dox and Dox-ICI groups (p = 0.493). In the Dox group, LVEF decreased to 59 ± 6% (Δ −7 ± 1.3%, p < 0.001) and LVGLS decreased from −17.3 ± 3.2% to −15.4 ± 3.2% (Δ −10.1 ± −1.9%, p < 0.001) at six months. In the Dox-ICI group, LVEF decreased to 55 ± 9% (Δ −9 ± 2.1%, p < 0.001), along with a significant decrease in LVGLS (from −18.6 ± 1.9% to −15.3 ± 3.6%, Δ −12.4 ± −2.4%, p < 0.001). Over a median follow-up of 192 days, there were no cases with clinical manifestations of fulminant myocarditis. In the Dox group, definite and probable CTRCD were observed in seven (10.1%) and five (7.4%) patients, respectively. In the Dox-ICI group, definite and probable CTRCD were observed in four (19%) and four (19%) patients, respectively. The total number of patients who developed CTRCD was significantly higher in the Dox-ICI group than in the Dox group (38.1% vs. 17.4%, p = 0.042). Serum troponin-T level was significantly higher in the Dox-ICI group than in the Dox group (53.3 vs. 27.5 pg/mL, p = 0.023). Conclusions: ICIs may increase the risk of CTRCD when used with cardiotoxic agents. CTRCD should be monitored in patients treated with ICIs by cardiac biomarkers and echocardiography, including LV-GLS.


Performance of breast cancer screening methods and modality among Chinese women: a report from a society-based breast screening program (SBSP) in Shanghai.
To evaluate the screening performance of individual and combined use of clinical breast examination, ultrasonography and mammography in Chinese women, we conducted a biennial breast cancer screening program among 14,464 women aged 35 to 74 years old who lived in Qibao County, Minhang district of Shanghai, China, between May 2008 and Sept 2012. All participants were submitted to clinical breast examination, and then women with positive results and all women at age of 45-69 years old were preformed breast ultrasonography and mammography. The examination results were compared against pathological findings as the gold standard of reference. A total of 66 women were diagnosed with breast cancer in the two rounds of the screening, yielding an incident rate of 194 per 100,000 person-years. The sensitivity of clinical breast examination, ultrasonography and mammography alone were 61.4%, 53.7% and 67.3%, respectively. While mammography performed better in elder age groups and hormone receptor positive disease groups, ultrasonography had a higher sensitivity in younger age group and did not differ in sensitivity by estrogen receptor or progesterone receptor status. Combined use of the two imaging examinations increased the sensitivity in almost all age groups, but had a higher sensitivity in hormone receptor positive cancers than in those negative. Our results suggest that the Qibao modality is an effective strategy for breast cancer screening among Chinese women, especially for early detection of elder and hormone receptor positive breast cancer.


Antibiotics use evaluation among hospitalized adult patients at Jimma Medical Center, southwestern Ethiopia: the way to pave for antimicrobial stewardship.
An irrational antibiotic use is a common problem in developing countries like Ethiopia, which makes empiric antibiotics use difficult. It is considered to be the greatest health problem in our time and future unless intervened. Therefore, this study aimed to assess the patterns of antibiotics use among hospitalized adult patients to pave the way for antimicrobial stewardship. A hospital-based prospective observational study was conducted at Jimma Medical Center, southwestern Ethiopia, from 30 October 2020 to 29 January 2021 with 360 adult hospitalized patients participating. A semi-structured questionnaire and consecutive sampling technique was used for data collection. The data were collected through medical record reviews and patient interviews. The collected data were entered into Epi-data and exported to SPSS® version 23.0 for analysis. Days of therapy (DOT) and essential medicine lists "Access, Watch, and Reserve (AWaRe)" antibiotics classification were used to assess antibiotic use pattern among participants. The majority of study participants were females (55.3%), attended formal education (59.4%), and live in rural areas (61.4%) with mean age ± (SD) of 37.65 ± (16.75). The overall rate of antibiotics consumption during the study was 111 days of therapy per 100 bed-days and about two-thirds (66%) of the prescribed antibiotics were from the "Watch" group antibiotics. The indicator level of antibiotics use for "Access" group antibiotics was 34% in this study based on the World Health Organization Essential Medicine List. Cephalosporins were the most commonly used class of antibiotics (93.9%). Higher antibiotics exposure and their consumption frequently observed among adult hospitalized patients in the study setting. There was a rapid increase in "Watch" group antibiotics use and about two-thirds of the prescribed antibiotics were from this group. The third-generation cephalosporin were the most commonly used class of antibiotics. Generally, higher consumption and inappropriate antibiotics use among hospitalized adult patients showed the need for urgent interventions by implementing Antimicrobial Stewardship Programs in hospitals.


Secondary intraocular lenses in eyes with aphakia or dislocated IOL: impact of suture fixation on early and late complications.
Secondary intraocular lens (IOL) implantation is exposed to an increased risk of complications, including endophthalmitis and retinal detachment. The present analysis compares the outcomes and complications experienced in our own series of patients. We retrospectively reviewed a consecutive series of secondary posterior chamber IOL implantations performed in a single centre, two surgeon setting over a period of 8 years and with a follow up-time of at least 4 months. Between 1997 and 2005, 75 patients received a sulcus-supported secondary IOL without suture fixation, whereas suture fixation was required in 137 instances. Visual acuity improved in both groups (group 1: from 0.36 +/- 0.39 (0.01-1.2) to 0.73 +/- 0.33 (0.02-1.0; p = 0.18); group 2: from 0.33 +/- 0.34 (0.02-1.0) to 0.46 +/- 0.33 (0.01-1.0; p = 0.006), but more pronounced in eyes not requiring suture fixation (p = 0.012). IOL placement was more likely to be combined with endophacoemulsification in the not suture-fixed IOLs (12.7 vs. 5.3 %). In contrast, retinal tears (10.6 vs. 8.6 %, respectively) and retinal detachment (5.3 vs. 2.2 %, respectively) were equally distributed. In the early postoperative phase, IOP was lower in suture-fixed eyes, which showed a higher incidence of minor intraocular haemorrhages and cystoid macular edema (5.3 vs. 8.0 %); late complications up to 5 years postoperatively were equally distributed. A preoperatively less complicated anterior segment situation and a lower incidence of postoperative macular edema may account for a better visual outcome after placement of a sulcus supported IOLs without suturing. If required, suture fixation may be performed without exposing the eye to an increased risk of late postoperative complications.


Water temperature variability at culvert replacement sites and river thermal impacts related to the removal of an old sediment pond: application on the Barnet Brook and a tributary of the Nerepis River (New Brunswick, Canada).
Culverts are very important hydraulic structures for stream crossing, and they come in various shapes and materials. There are generally two different types of culverts, i.e., closed bottom and open bottom structures. In the present study, two closed bottom culverts have been replaced by open bottom structures (arch culverts) during the summer of 2018. The objective of the present study was to analyze water temperature variability along the impacted sites, one year after the replacement, i.e., 2019 to assess potential impacts of the streamside vegetation removal on the thermal conditions of these streams. Results showed a significant (p < 0.05) change in mean summer temperatures at both sites. Changes in stream temperatures at Barnet Brook were attributed to the removal of an old sediment pond, whereas changes in stream temperatures at the tributary of the Nerepis River were likely due to the removal of the streamside vegetation. Increases in water temperatures (> 4 °C) were more pronounced during low flow periods compared to high flow conditions at both sites.


Inhibition of Tamm-Horsfall glycoprotein induction of alkaline phosphatase in cystic fibrosis fibroblasts by medium conditioned by normal cells.
It is confirmed that the level of alkaline phosphatase in fibroblasts derived from cystic fibrosis patients can be induced many-fold by growing the cells in the presence of Tamm-Horsfall glycoprotein. It is further shown that normal fibroblasts produce a "CF corrective factor" which markedly inhibits this phenomenon. These observations support a previous hypothesis on the nature of the metabolic defect in cystic fibrosis.


Drinks consumed by 18-month-old children: are current recommendations being followed?
To examine the types of drinks consumed by children at 18 months of age, determine any associations with socio-demographic characteristics and investigate the use of a bottle for providing these drinks. A total of 1026 randomly chosen children from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) were studied. As part of a dietary diary completed when their children were 18 months of age, mothers were asked to record all drinks consumed over a 24 h period and to report the containers used to give these drinks. Socio-demographic characteristics were obtained via self-completion questionnaire. Dietary records were available for 1026 children at 18 months. A wide variety of drinks were given at this age. In all, 64% of children had received at least one drink in a bottle and 10% solely used a bottle. Bottle users consumed a significantly greater volume of milk drinks compared to those who used a cup or other container. The types of drinks consumed and adherence to the guidelines on weaning were associated with several socio-demographic characteristics. In particular, children with mothers of lower educational level were more likely to receive fizzy drinks and low-calorie soft drinks, more likely to drink from a bottle, and less likely to drink from a cup. We have shown that certain groups of mothers with 18-month-old children are not following the current guidelines on weaning. Assuming these guidelines have scientific validity, it is clear that nutritional education needs to be targeted at these mothers to help them feed their children in the optimal way, to protect from nutritional deficiencies, possible later obesity and poor dental health. University of Bristol.


Real-time magnetic resonance imaging-guided stenting of aortic coarctation with commercially available catheter devices in Swine.
Real-time MR imaging (rtMRI) is now technically capable of guiding catheter-based cardiovascular interventions. Compared with x-ray, rtMRI offers superior tissue imaging in any orientation without ionizing radiation. Translation to clinical trials has awaited the availability of clinical-grade catheter devices that are both MRI visible and safe. We report a preclinical safety and feasibility study of rtMRI-guided stenting in a porcine model of aortic coarctation using only commercially available catheter devices. Coarctation stenting was performed wholly under rtMRI guidance in 13 swine. rtMRI permitted procedure planning, device tracking, and accurate stent deployment. "Active" guidewires, incorporating MRI antennas, improved device visualization compared with unmodified "passive" nitinol guidewires and shortened procedure time (26+/-11 versus 106+/-42 minutes; P=0.008). Follow-up catheterization and necropsy showed accurate stent deployment, durable gradient reduction, and appropriate neointimal formation. MRI immediately identified aortic rupture when oversized devices were tested. This experience demonstrates preclinical safety and feasibility of rtMRI-guided aortic coarctation stenting using commercially available catheter devices. Patients may benefit from rtMRI in the future because of combined device and tissue imaging, freedom from ionizing radiation, and the ability to identify serious complications promptly.


The longitudinal changes of serum JKAP and IL-17A, and their linkage with anxiety, depression, and cognitive impairment in acute ischemic stroke patients.
Our previous study discovers that Jun N-terminal kinase pathway-associated phosphatase (JKAP) is dysregulated and negatively links with the disease severity in acute ischemic stroke (AIS) patients. This study intended to further evaluate the linkage of JKAP and interleukin (IL)-17A with anxiety, depression, and cognitive impairment in AIS patients. Serum JKAP and IL-17A levels in 120 AIS patients at admission, 1st (D1), 3rd (D3), 7th (D7) day after admission, and from 20 controls, were detected by ELISA. Hospital Anxiety and Depression Scale (HADS) and Mini-Mental State Examination (MMSE) were assessed in AIS patients at discharge. JKAP (p < 0.001) was reduced, but IL-17A (p < 0.001) was increased in AIS patients versus controls, and negatively correlated with each other in AIS patients (p = 0.014). In AIS patients, JKAP was reduced from baseline to D1 and then increased to D7 (p < 0.001), while IL-17A exhibited an opposite trend (p < 0.001). Notably, JKAP at D3 was negatively linked with HADS-anxiety score (p = 0.044), then decreased JKAP at D3 (p = 0.017) and D7 (p = 0.037) related to increased anxiety occurrence. However, JKAP was not linked to HADS-depression score or depression occurrence. Besides, JKAP at multiple time points were positively associated with MMSE score (all p < 0.05); decreased JKAP at D3 (p = 0.017) and D7 (p = 0.026) related to raised cognitive impairment occurrence. JKAP initially decreases then shows an increasing trend after disease onset, and its decrement relates to elevated IL-17A, anxiety and cognitive impairment in AIS patients.


Clearance of Mycoplasma genitalium and Trichomonas vaginalis Among Adolescents and Young Adults With Pelvic Inflammatory Disease: Results From the Tech-N Study.
Current pelvic inflammatory disease (PID) treatment effectively treats Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT). However, coverage may be inadequate for Mycoplasma genitalium (MG)/Trichomonas vaginalis (TV) infections. We compared the longitudinal MG and TV outcomes with NG/CT outcomes for women enrolled in a longitudinal randomized controlled trial to optimize outcomes after PID. The prevalences of CT and NG were lower at 30- and 90-day follow-up compared with the prevalence at the time of diagnosis. No significant difference was observed for MG (odds ratio, 0.95; 0.86-1.04; P = 0.265) and TV (odds ratio, 0.89; 0.75-1.04; P = 0.146) over time for both treatment groups, showing that persistence and/or reinfection with MG and TV occurs more frequently than with CT or NG after treatment of PID using current national treatment guidelines.


Potential of guava leaves for mitigating methane emissions and modulating ruminal fermentation characteristics and nutrient degradability.
Guava leaves (Psidium guajava, GL), a high-phenolic- and flavonoid-containing plant resource capable of substituting the high-quality forage, may help in mitigating ruminal methane (CH4) emission without adverse impact on nutrient degradability if supplemented at an appropriate level. In order to test this hypothesis, rumen fermentation, CH4 production, and nutrient degradability of GL either solely or as a substitute of berseem hay (Trifolium alexandrinum, BH) were evaluated in a diet containing 50:50 concentrate to roughage. Five different levels of GL (0, 12.5, 25, 37.5, and 50%) were tested in vitro after 24 h incubation using a semi-automated gas production (GP) system. The current findings indicated that merely the presence of GL resulted in significantly lower values for cumulative GP (P < 0.001), CH4 emission (P < 0.05), truly degraded dry matter (TDDM; P < 0.001), truly degraded organic matter (TDOM; P < 0.001), and ammonia nitrogen (NH3-N) concentration (P < 0.001); however, pH (P < 0.001) and partitioning factor (P < 0.001) were higher. The total and individual volatile fatty acid (VFA) concentrations were drastically declined with GL as compared to BH (P < 0.05). A negative linear correlation was recorded between the levels of GL and GP including CH4 production (P < 0.05). The addition of GL up to 25% did not pose any negative effect on both TDDM and TDOM values along with NH3-N concentration. In addition, the inclusion of GL up to 25% did not affect the total or individual VFA concentration. Conclusively, in a medium concentrate diet, use of 25% GL and 25% BH in animal diet could be a promising alternative for mitigating the CH4 production without any deleterious effect on nutrient degradability.


Disease severity scoring systems in mucosal lichen planus: A systematic review.
Several scoring systems have been developed to evaluate disease severity in mucosal lichen planus, but only a few have been validated to ensure reproducible and accurate assessment of disease severity. The current systematic review was undertaken to identify clinical severity scoring systems in mucosal lichen planus that have undergone validity or reliability testing and to describe their operating characteristics. We performed a bibliographic search in five databases from their inception to October 2022 for severity scoring systems in mucosal lichen planus that have undergone validity or reliability tests. Quality assessment was conducted using the Joanna Briggs Institute Critical Appraisal tools. We have included 118 studies and identified 11 clinical severity scoring systems for oral lichen planus that have undergone validity or reliability testing. Of these, the most reported were the Thongprasom score, the Oral Disease Severity Score (ODSS) and the REU (Reticular/hyperkeratotic, Erosive/erythematous, Ulcerative) scoring systems. We did not identify clinical scoring systems for extraoral mucosal lichen planus that have undergone validity or reliability testing. The ODSS and REU scoring systems have undergone the highest number of validation attempts and reliability assessments for oral lichen planus respectively. However, we have identified numerous factors that have hampered the universal adoption of a standardised scoring system. There is a need for the development and validation of scoring systems for extraoral mucosal lichen planus.


Denervation alters the size, number, and distribution of clusters of acetylcholine receptor-like molecules on frog cardiac ganglion neurons.
Acetylcholine receptor (AChR)-like molecules are found in clusters on the surface of parasympathetic neurons in the frog cardiac ganglion. Electron microscopy of immunoperoxidase-stained tissue reveals that in normally innervated ganglia most of these clusters are located at synaptic sites. Denervation for 2-3 weeks results in a 64% reduction in the total surface area occupied by AChR-like clusters; this change is brought about by the combined effects of a 4-fold decrease in cluster size and a 30% increase in cluster number. Denervation also changes the distribution of AChR-like clusters: clusters, normally restricted to portions of the cell surface, are more widely distributed following denervation. Denervation of amphibian skeletal muscle for a comparable period of time has no effect on the size or the number of synaptic clusters of AChRs. These results suggest that AChRs in nerve and in muscle are regulated differently by innervation.


Industry funding of the FDA: effects of PDUFA on approval times and withdrawal rates.
The development of new therapies is a crucial component of efforts to improve healthcare. Because drug development and FDA regulatory review have historically been lengthy and costly processes, the US Congress passed a series of legislative acts, beginning in 1992, known collectively as the Prescription Drug User Fee Acts (PDUFA), which sought to expedite the FDA drug-review process. Here, we review data on drug approvals and drug-approval times, both as a whole and by therapeutic class, which demonstrate that implementation of the PDUFAs led to substantial incremental reductions in approval times beyond what would have been observed in the absence of these legislative acts. In addition, our preliminary examination of the trends in the number of new molecular entity withdrawals, frequently used as a proxy to assess the FDA's safety record, suggests that the proportion of approvals ultimately leading to safety withdrawals prior to PDUFA and during PDUFA I and II were not statistically different.


A school-based primary prevention group for children with alterations in health status.
The implementation of primary prevention measures for the positive mental health of children has been identified by psychiatric nursing leaders as a priority for child psychiatric nurses. Promoting positive mental health behaviors in school-aged children is facilitated by establishing a helping relationship within the context of small-group activity situated in the child's natural school setting. The authors describe the theory and process of establishing a time-limited, closed group in a school setting, for 10 children who were experiencing some alteration in health status.


GuaB activity is required in Rhizobium tropici during the early stages of nodulation of determinate nodules but is dispensable for the Sinorhizobium meliloti-alfalfa symbiotic interaction.
The guaB mutant strain Rhizobium tropici CIAT8999-10T is defective in symbiosis with common bean, forming nodules that lack rhizobial content. In order to investigate the timing of the guaB requirement during the nodule formation on the host common bean by the strain CIAT899-10.T, we constructed gene fusions in which the guaB gene is expressed under the control of the symbiotic promoters nodA, bacA, and nifH. Our data indicated that the guaB is required from the early stages of nodulation because full recovery of the wild-type phenotype was accomplished by the nodA-guaB fusion. In addition, we have constructed a guaB mutant derived from Sinorhizobium meliloti 1021, and shown that, unlike R. tropici, the guaB S. meliloti mutant is auxotrophic for guanine and induces wild-type nodules on alfalfa and Medicago truncatula. The guaB R. tropici mutant also is defective in its symbiosis with Macroptilium atropurpureum and Vigna unguiculata but normal with Leucaena leucocephala. These results show that the requirement of the rhizobial guaB for symbiosis is found to be associated with host plants that form determinate type of nodules.


Kawasaki syndrome.
Kawasaki syndrome is an acute multisystem inflammatory disease of young children first described by Tomasaku Kawasaki in the Japanese literature in 1967. He reported 50 cases of this entity under the rubric of acute febrile mucocutaneous lymph node syndrome, a designation that has more recently been superseded by the eponym Kawasaki syndrome. The disorder was further delineated and brought to the attention of American pediatricians in 1974. Recognition of the syndrome followed rapidly, and Melish, Hicks and Larson published the first series of American cases from Hawaii in 1976. Subsequently, Kawasaki syndrome has been documented worldwide. Although the disorder is known to be a systemic vasculitis with predilection for the coronary arteries, the etiology has remained obscure despite intense investigative efforts.


Improvement of intertrochanteric bone quality in osteoporotic female rats after injection of polylactic acid-polyglycolic acid copolymer/collagen type I microspheres combined with bone mesenchymal stem cells.
Osteoporosis mainly involves cancellous bone, and the spine and hip, with their relatively high cancellous bone to cortical bone ratio, are severely affected. Studies of bone mesenchymal stem cells (BMSCs) from osteoporotic patients and animal models have revealed that osteoporosis is often associated with reduction of BMSCs' proliferation and osteogenic differentiation. Our aim was to test whether polylactic acid-polyglycolic acid copolymer(PLGA)/collagen type I(CoI) microspheres combined with BMSCs could be used as injectable scaffolds to improve bone quality in osteoporotic female rats. PLGA microspheres were coated with CoI. BMSCs of the third passage and were cultured with PLGA/CoI microspheres for seven days. Forty three-month-old female non-pregnant SD rats were ovariectomized to establish osteoporotic animal models. Three months after being ovariectomized, the osteoporotic rats were randomly divided into five groups: SHAM group, PBS group, cell group, microsphere (MS) group, and cell+MS group. Varying materials were injected into the intertrochanters of each group's rats. Twenty rats were sacrificed at one month and three months post-op, respectively. The femora were harvested in order to measure the intertrochanteric bone mineral density (BMD) with DEXA and trabecular thickness (Tb.Th), percentage of trabecular area (%Tb.Ar), bone volume fraction (BV/TV) and trabecular spacing (Tb.Sp) with Micro CT. One-way ANOVA and Kruskal-Wallis tests were used. BMSCs seeded on PLGA/CoI microspheres had a nice adhesion and proliferation. At one month post-op, the BMD (0.33 ± 0.01 g/cm(2)), Tb.Th (459.65 ± 28.31 μm), %Tb.Ar (9.61 ± 0.29 %) and Tb.Sp (2645.81 ± 94.91 μm) of the cell+ MS group were better than those of the SHAM group and the cell group. At three months post-op, the BMD (0.32 ± 0.01 g/cm(2)), Tb.Th (372.81 ± 38.45 μm), %Tb.Ar (6.65 ± 0.25 %), BV/TV (6.62 ± 0.25 %) and Tb.Sp (1559.03 ± 57.06 μm) of the cell + MS group were also better than those of the SHAM group and the cell group. The PLGA/CoI microspheres combined with BMSCs can repair bone defects more quickly. This means that PLGA/CoI microspheres combined with BMSCs can promote trabecular reconstruction and improve bone quality in osteoporotic rats. This scaffold can provide a promising minimally invasive surgical tool for enhancement of bone fracture healing or prevention of fracture occurrence which will in turn minimize complications endemic to patients with osteoporosis.


Hypermethylation of the DNA mismatch repair gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer.
It remains to be investigated whether the aberrant methylation of DNA repair genes plays a pathogenic role in BRAF mutation-promoted tumorigenesis of papillary thyroid cancer (PTC). In the current study, the promoter methylation status of 23 DNA repair genes in relation to clinicopathologic characteristics and BRAF mutation was examined in PTC tumors using methylation-specific polymerase chain reaction. Among the 38 PTC tumors examined, 3 of 23 DNA repair genes were hypermethylated, including the hMLH1 gene in 8 of 38 samples (21%), the PCNA gene in 5 of 38 samples (13%), and the OGG1 gene in 2 of 38 samples (5%). Methylation of these genes was also found in some thyroid cancer cell lines. Methylation of the hMLH1 gene in particular was found to be associated with lymph node metastasis of PTC (5 of 8 samples [63%] in the methylation group vs 3 of 30 samples [10%] in the nonmethylation group; P = .0049). Methylation of the hMLH1 gene was also found to be associated with the T1799A BRAF mutation in PTC (6 of 19 samples (32%) in the BRAF mutation-positive group vs 2 of 19 samples (11%) in the BRAF mutation-negative group; P = .042). The data from the current study suggest that, as shown previously in colon cancer, aberrant methylation of the hMLH1 gene may play a role in BRAF mutation-promoted thyroid tumorigenesis.


Dopamine-like action of nicotine: lack of tolerance and reverse tolerance.
Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra became briefly sedated and hypothermic after the acute injection of nicotine s.c. (0.4 or 0.8 mg/kg free base). When nicotine was repeated 5 days per week there was rapid tolerance for the sedation and slower tolerance for the hypothermia and the lesioned animals began to rotate ipsiversively after each injection. Stereotypic behavior was also noted. Rats injected with nicotine 5 days per week and nigrally lesioned on the 24th day rotated promptly on their first postoperative injection of nicotine. The nicotinic antagonist, mecamylamine (1.0 mg/kg i.p.), completely blocked the induced rotation. The appearance of rotation did not seem to depend on tolerance to sedation. The direction of rotation indicated enhancement of activity in the intact nigrostriatal system. However, 10 min after the acute injection of 0.8 mg/kg nicotine no change was found in the ratios of dopamine to its metabolites DOPAC and homovanillic acid in the substantia nigra, caudate-putamen, nucleus accumbens, olfactory tubercle, frontal cortex, or ventral tegmental area. Rats given 0.4 or 0.8 mg/kg nicotine 5 days per week and either lesioned prior to nicotine or lesioned during the third week rotated during the sixth week without any sign of tolerance. One day after the 30th injection in intact or lesioned rats the ratios of dopamine to its metabolites did not differ from those in saline controls on either the right or left side of any of the regions examined. There was no evidence of a change in dopamine metabolism after an acute challenge with nicotine or of a sustained change after repeated injection. The possibility remains that repeated nicotine modifies the dopaminergic response to nicotine without causing a sustained change in metabolism.


Illustrating triangulation in mixed-methods nursing research.
Graham R Williamson discusses the concept of triangulation in data collection and analysis in mixed-methods research, and reflects upon how this contributed to a deeper understanding when he used it in his work


Contrast between the pharmacokinetics of two formulations of cephalexin after intramuscular administration in cattle.
Two commercial formulations of cephalexin were administered intramuscularly to five heifers and five bulls in a balanced crossover design. Statistically significant and clinically important differences were detected between the two formulations of cephalexin. These results suggest that 24 h dose intervals would be appropriate with only one of the formulations and that the recommended dose rates for each product may need to be reviewed.


Effect of chemoreceptor denervation on the pulmonary vascular response to atelectasis.
Six dogs anesthetized with 30 mg/kg pentobarbital were ventilated after differential cannulation of the main stem bronchi. Following sternotomy, blood flow was monitored by electromagnetic flow probes on the left pulmonary artery (QL) and on the pulmonary trunk or aorta (QT). Following 10 min of bilateral 100% O2, QL was 37.4 +/- 5.8% of QT. When left lung atelectasis was induced while the right lung remained on 100% O2, PaO2 remained above 75 mm Hg and QL fell to 26.1 +/- 5.0% of QT. However, when the right lung was ventilated with room air while the left lung remained atelectatic, PaO2 fell to 50.0 +/- 2.6 mm Hg and QL rose to 36.7 +/- 6.2% of QT. Six dogs which had undergone peripheral chemoreceptor denervation prior to these experiments showed a similar decrease in perfusion of the atelectatic left lung when the right lung was ventilated with 100% O2, but did not increase blood flow to the atelectatic lung during systemic hypoxemia. Thus, the increased blood flow to the atelectatic lung which occurs during systemic hypoxemia appears to be mediated by the arterial chemoreceptors.


Predation pressure on an imperfect Batesian micicry complex in the presence of alternative prey.
Differential predation pressure and the probability of predation on a Batesian mimicry complex and on alternative prey were estimatedin a field experiment. The mimicry complex was composed of a noxious model (Eleodes obscura (Say)) and a palatable mimic (Stenomorpha marginata (LeConte)). House crickets (Acheta domesticus) (Linn.) were used as alternative prey. The experiment was conducted for 23 nights in August and September to approximate the peak seasonal activity time period during which both models and mimics normally are exposed to predation while foraging and depositing eggs. Each night thirty prey in ratios of 16 models: 7 mimics: 7 crickets were exposed for 2.5 h to a suite of predators consisting of pallid bats (Antrozous pallidus), striped skunks (Mephitis mephitis) and ringtails (Bassariscus astutus) that had free access to the prey. The model-mimic ratio was similar to that found in nature. Predators obtained prey on 11 of the 23 nights and preferred the alternative prey (crickets) in proportions higher than was expected from a predation rate that was equal on all species of prey. Mimics were taken by predators at a rate proportional to their abundance, while models were taken at a rate considerably lower than their relative abundance. This suggests that at least some of the predators could distinguish between models and mimics and were willing to eat the mimics at higher frequencies than they were willing to eat the models. However, although the mimicry is not perfect with respect to the entire predator suite, the mimics still gain an advantage by resembling the models, compared to the predation levels on the alternate prey.


Effects of Music Therapy on Spiritual Well-Being among Patients with Advanced Cancer in Palliative Care: A Meta-Analysis of Randomized Controlled Trials.
Patients with advanced cancer in palliative care often experience physical and psychological symptoms that negatively impact their quality of life (QoL) and spiritual well-being. Music therapy can be used for symptom management in these patients. However, the effectiveness is uncertain. To determine the effectiveness of music therapy on spiritual well-being, QoL, pain, and psychological distress using randomized controlled trials (RCTs). A systematic search was conducted in EMBASE, PubMed, Cochrane Library, CINAHL, Web of Science, and the ClinicalTrial.gov registry up to September 2022. The meta-analysis included seven RCTs with a total of 747 advanced cancer patients. Music therapy was found to significantly improve spiritual well-being with a mean difference of 0.43 (95% CI: 0.25 to 0.61, P < .001) in the intervention group compared to the control group. However, no significant group differences were found between the intervention and control groups for QoL (SMD: 0.53, 95% CI: -0.12 to 1.13, P = .11), pain (MD: -0.81, 95% CI: -2.06 to 0.44, P = .20), and psychological distress (SMD: -0.05, 95% CI: -0.41 to 0.32, P = .81). Music therapy can effectively improve the spiritual well-being of palliative care patients. However, its beneficial effects on QoL, pain, and psychological distress were minimal. Music therapy interventions can be introduced to help patients deal with spiritual/existential needs. Future studies should identify optimal characteristics of music therapy interventions to aid in enhancing the quality of palliative care for patients with advanced cancer.


Data on association of ankle pressure and ankle brachial index of symptomatic and contralateral lower extremities with overall and cardiovascular mortality in patients with lower extremity peripheral artery disease.
Data on survival curves for overall survival and freedom from cardiovascular death at different ankle brachial index (ABI) and ankle pressure (AP) are shown separately for symptomatic and contralateral lower limbs in 721 patients with lower extremity peripheral artery disease at up to 7 years follow-up. Cox regression analysis with confounding factors for ABI and AP are also shown. Dates and causes of death were collected from the Finnish national statistics registry.


Correlation of KIF3A and OVOL1, but not ACTL9, with atopic dermatitis in Chinese pediatric patients.
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in Chinese pediatric patients. To date, the genetic susceptibility to AD in this population has not been fully clarified. Three single nucleotide polymorphisms have previously been associated with AD in Europeans, rs2897442 (KIF3A), rs479844 (OVOL1) and rs2164983 (ACTL9). To verify the correlation between AD and these three SNPs in the Chinese pediatric population, we conducted a case-control study including 235 pediatric patients with AD and 200 health controls. We confirmed the correlation between rs2897442 and rs479844 and AD in this population at both the genotype and allele levels. Statistical analysis showed that the C allele of rs2897442 is associated with an increased risk of developing AD, while the A allele of rs479844 is associated with a reduced risk. No correlation between rs2164983 and AD was identified. Our study indicates that KIF3A and OVOL1 are involved in the development of AD in the Chinese pediatric population.


Genotoxicity studies of di(2-ethylhexyl)phthalate and its metabolites in CHO cells.
The widely used plasticizer di(2-ethylhexyl)phthalate (DEHP), its hydrolysis products mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol, and also phthalic acid have been tested for clastogenic activity in cultured Chinese hamster ovary (CHO) cells. Only MEHP was found to cause chromosome damage. MEHP was without effect in the SCE and HGPRT mutation test in CHO cells. The clastogenicity of MEHP suggests a role for this compound in the observed carcinogenicity of DEHP and its positive effect in the dominant lethal assay.


Single-Atoms on Covalent or Metal-Organic Frameworks: Current Findings and Perspectives for Pollutants Abatement, Hydrogen Evolution, and Reduction of CO2.
Nowadays, attention to single-atoms and also porous structures like metal-organic frameworks (MOFs) and covalent-organic frameworks (COFs) for the preparation of high-performance material is expanding rapidly. These dazzling materials with unprecedented properties have lots of applications, especially as promising catalysts for organic pollutants abatement, hydrogen evolution, reduction of CO2, etc. To provide an in-depth understanding, in this mini-review, we begin with a brief description and a general background about single-atoms, COFs, as well as MOFs. After considering some fundamentals, the synergism effects, advantages, and their applications are discussed.


Leydig cell differentiation induced by stimulation with HCG and HMG in two patients affected with hypogonadotropic hypogonadism.
In order to elucidate the ultrastructural characteristics of the precursor cell of Leydig cells and its subsequent differentiation, testicular biopsies from two patients with hypogonadotropic hypogonadism, obtained prior to and after treatment with HCG and HMG, were studied in comparison with those of prepubertal, pubertal and postpubertal testes. Prior to HCG and HMG stimulation, the testicular interstitium of both patients showed the following spindle-cell-types: Fibroblasts, myofibroblasts and a cell-type similar to the myofibroblast but differing from it by the arrangement of microfilaments and the development of the smooth endoplasmic reticulum as well as lipid droplets. It may be considered the precursor of Leydig cells. In the following stages of differentiation observed in the biopsies after treatment, there is a progressive involution of microfilaments and rough endoplasmic reticulum, a transient period of hyperplasia of the Golgi complex, and the definitive development of cell components involved in steroid biosynthesis, such as the smooth endoplasmic reticulum, polymorphic mitochondria with tubular cristae, lipid droplets and diverse lysosomal bodies. From early stages of differentiation, gap junctions occurred between the cells. Numerous axon profiles were also present among the cells. Only in a small percentage of cells did vesicle-bearing axons closely appose the Leydig cell membrane.


Prenatal diagnosis of glucose-6-phosphate-dehydrogenase deficiency.
Prior to the development of the DNA-based technology reliable prenatal diagnosis of G6PD deficiency was not possible. We show that, using PCR amplification and restriction endonuclease digestion, prenatal diagnosis is possible. We have now been able to determine that the male fetus of a mother heterozygous for G6PD Mediterranean had inherited the maternal X chromosome with the normal G6PD gene.


Human leucocyte antigen-defined microchimerism early post-transplant does not predict for stable lung allograft function.
Microchimerism is the presence of foreign cells in an individual below 1% of total cells, which can occur in the setting of solid organ transplantation. This study quantitated donor-derived cellular subsets longitudinally in human leucocyte antigen (HLA)-mismatched lung transplant recipients (LTR) during the first post-operative year and evaluated the pattern of peripheral microchimerism with clinical outcomes. Peripheral blood mononuclear cells (PBMC) isolated from non-HLA-B44 LTR who received HLA-B44 allografts were sorted flow cytometrically into three cellular subsets. Real-time quantitative polymerase chain reaction (q-PCR) demonstrated that donor-derived HLA-B44 microchimerism is a common phenomenon, observed in 61% of patients. The level of donor-derived cells varied across time and between LTR with frequencies of 38% in the B cells/monocytes subset, 56% in the T/NK cells subset and 11% in the dendritic cells (DC) subset. Observations highlighted that microchimerism was not necessarily associated with favourable clinical outcomes in the first year post-lung transplantation.


A new technique for selective cannulation of the sino-atrial node artery.
The electrical activity of the sino-atrial node was studied after the selective cannulation of its artery in the intact open-chest dog. After tetrodotoxin infusion and despite cardiac arrest, a slow rhythmic activity was recorded from the sinus epicardial electrode.


Influence of purines on endothelial high energy phosphates.
It was demonstrated that extracellularly available adenosine, which is reported to protect the endothelium during ischaemia and reperfusion [8], is predominantly uptaken and salvaged by HUVECs, thereby enriching the adenine phosphate pool. In this way adenosine could contribute to a regeneration of metabolically disturbed cells via increasing the intracellular ATP. In contrast, all other purines offered can hardly be used by HUVECs to increase the pool of energy rich phosphates.


[Management of post-traumatic facial paralysis. A decision based on a series of 85 cases].
To review patient selection and factors affecting the decision for surgical or non-surgical management of patients with trauma-induced facial nerve palsy. Retrospective review of 85 consecutive cases occurring over a 6-year period. Between 1984 and 1990, 85 cases of facial nerve palsy following trauma were treated. Patient assessment included clinical, audiological, radiological and EMG examinations. Depending on test results, patients were either given medical treatment or underwent total facial nerve decompression surgery. Recovery was achieved in all 33 medically treated patients. Among the 52 surgically-treated patients (61.2%), 47 had immediate facial nerve palsy at admission (90.4%). Onset of facial palsy was delayed in 5 others, including 3 for whom the delay to onset was unknown. Surgical accesses used were the middle fossa and transmastoidal (60%), translabyrinthine (11%), and pure transmastoidal (29%) routes depending on hearing loss, location of fracture line and general patient condition. Lesions were predominantly found in the geniculate ganglion area. A nerve gap was found in only 13.5% of the cases. Two years post-operatively, 92.3% of the patients had grade I-III recovery. No grade V or VI cases were observed. The rarity of severe nerve lesions encountered in surgically-treated patients raises the question of better candidate selection for surgery. At present, imaging techniques, particularly radiology, can help to choose the best indication. Immediate total facial palsy associated with a clear-cut fracture going through the Fallopian canal is perhaps the only case requiring surgery. When the delay of onset is unknown, an EMG indicating a total denervation process is the decisive argument.


Principles of Pituitary Surgery.
Since the description of a transnasal approach for treatment of pituitary tumors, transsphenoidal surgery has undergone continuous development. Hirsch developed a lateral endonasal approach before simplifying it to a transseptal approach. Cushing approached pituitary tumors using a transsphenoidal approach but transitioned to the transcranial route. Transsphenoidal surgery was not "rediscovered" until Hardy introduced the surgical microscope. An endoscopic transsphenoidal approach for pituitary tumors has been reported and further advanced. We describe the principles of pituitary surgery including the key elements of surgical decision making and discuss the technical nuances distinguishing the endoscopic from the microscopic approach.


Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases.
β-Lactam antibiotics are the first choice for the treatment of most bacterial infections. However, the increased prevalence of β-lactamases, in particular extended-spectrum β-lactamases, in pathogenic bacteria has severely limited the possibility of using β-lactam treatments. Combining β-lactam antibiotics with β-lactamase inhibitors can restore treatment efficacy by negating the effect of the β-lactamase and has become increasingly important against infections caused by β-lactamase-producing strains. Not surprisingly, bacteria with resistance to even these combinations have been found in patients. Studies on the development of bacterial resistance to β-lactam/β-lactamase inhibitor combinations have focused mainly on the effects of single, chromosomal or plasmid-borne, β-lactamases. However, clinical isolates often carry more than one β-lactamase in addition to multiple other resistance genes. Here, we investigate how the evolutionary trajectories of the development of resistance to three commonly used β-lactam/β-lactamase inhibitor combinations, ampicillin-sulbactam, piperacillin-tazobactam, and ceftazidime-avibactam, were affected by the presence of three common β-lactamases, TEM-1, CTX-M-15, and OXA-1. First-step resistance was due mainly to extensive gene amplifications of one or several of the β-lactamase genes where the amplification pattern directly depended on the respective drug combination. Amplifications also served as a stepping-stone for high-level resistance in combination with additional mutations that reduced drug influx or mutations in the β-lactamase gene blaCTX-M-15. This illustrates that the evolutionary trajectories of resistance to β-lactam/β-lactamase inhibitor combinations are strongly influenced by the frequent and transient nature of gene amplifications and how the presence of multiple β-lactamases shapes the evolution to higher-level resistance.


Decarboxylative Borylation and Cross-Coupling of (Hetero)aryl Acids Enabled by Copper Charge Transfer Catalysis.
We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.


Regulatory challenges facing closed-loop anesthetic drug infusion devices.
Closed-loop anesthetic drug infusion devices show great promise for improving the consistency and safety of general anesthesia. Despite the numerous reports demonstrating the feasibility and potential advantages of these systems in a research setting, a wide range of regulatory, business, and clinical issues will need to be resolved before a closed-loop anesthesia delivery product can be successfully introduced into the market and incorporated into general practice.


Combined effects of sample parameters on polymer charging due to electron irradiation: a contour simulation.
Combined effects of sample parameters on polymer charging due to electron irradiation are explored by a novel approach of contour in parallel computing. Transient processes of negative charging of a Kapton film sample irradiated by 10 keV electrons are simulated with a simultaneous scattering-transport model and the existing experimental secondary electron current. As a function of sample thickness and electron mobility, the contour maps are then presented of the steady-state leakage current and surface potential and the total charge accumulated in a charging process. It is found that the leakage current and surface potential behave similarly in the contour form, and the total charge has the local maximum with respect to the sample thickness. Generally, the sample thickness affects the charging process more than the electron mobility, but both have less influence in very strong and weak charging states. Accompanied by discussion of charge dissipation effects, this study offers a comprehensive insight into complicated charging phenomena in electron-based surface microscopy, analysis and measurement.


Retinal regions shape human and murine Müller cell proteome profile and functionality.
The human macula is a highly specialized retinal region with pit-like morphology and rich in cones. How Müller cells, the principal glial cell type in the retina, are adapted to this environment is still poorly understood. We compared proteomic data from cone- and rod-rich retinae from human and mice and identified different expression profiles of cone- and rod-associated Müller cells that converged on pathways representing extracellular matrix and cell adhesion. In particular, epiplakin (EPPK1), which is thought to play a role in intermediate filament organization, was highly expressed in macular Müller cells. Furthermore, EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces as well as to changes in cell size, shape, and filopodia characteristics. We here identified EPPK1 as a central molecular player in the region-specific architecture of the human retina, which likely enables specific functions under the immense mechanical loads in vivo.


The dynamic metabolic profile of Qi-Yu-San-Long decoction in rat urine using UPLC-QTOF-MSE coupled with a post-targeted screening strategy.
Qi-Yu-San-Long decoction (QYSLD) is a traditional Chinese medicine that has been clinically used in the treatment of non-small-cell lung cancer (NSCLC) for more than 20 years. However, to date, metabolic-related studies on QYSLD have not been performed. In this study, a post-targeted screening strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight full information tandem mass spectrometry (UPLC-QTOF-MSE) was developed to identify QYSLD-related xenobiotics in rat urine. The chemical compound database of QYSLD constituents was established from previous research, and metabolites related to these compounds were predicted in combination with their possible metabolic pathways. The metabolites were identified by extracted ion chromatograms using predicted m/z values as well as retention time, excimer ions, and fragmentation behavior. Overall, 85 QYSLD-related xenobiotics (20 prototype compounds and 65 metabolites) were characterized from rat urine. The main metabolic reactions and elimination features of QYSLD included oxidation, reduction, decarboxylation, hydrolysis, demethylation, glucuronidation, sulfation, methylation, deglycosylation, acetylation, and associated combination reactions. Of the identified molecules, 14 prototype compounds and 58 metabolites were slowly eliminated, thus accumulating in vivo over an extended period, while five prototypes and two metabolites were present in vivo for a short duration. Furthermore, one prototype and five metabolites underwent the process of "appearing-disappearing-reappearing" in vivo. Overall, the metabolic profile and characteristics of QYSLD in rat urine were determined, which is useful in elucidating the active components of the decoction in vivo, thus providing the basis for studying its mechanism of action.


[Antibody formation in the blood and respiratory tract secretions following one-time and repeat immunization with an inactivated influenza vaccine].
Eighty nine volunteers were under study. They were immunized by inactivated vaccine from influenza viruses A(H1N1)+A(H3N2) one time or every year during 4 to 6 years. Vaccine in dosage of 0.2 ml was applied intracutaneously. Under detailed clinical study deflections of health were not over standard. Accumulation of antibodies was determined to immunogens of the vaccine and to virus A/Leningrad/X/83(H3N2), which was in epidemic circulation 3 years later. Intensity of relative increase of antibodies with repeated immunization was 1.5 to 2 times lower. Maximum concentrations of antibodies were found in a week after vaccination. Immunization didn't cause change of titres of secretory antibodies and concentration of immunoglobulin isotopes G, M, A and E in sera and secretions.


Anesthesia for outpatient dermatologic cosmetic surgery: midazolam--low-dosage ketamine anesthesia.
Cardiovascular, respiratory, CNS, and postoperative effects of using low-dose ketamine and midazolam combined with local anesthesia during 40 outpatient cosmetic procedures are reviewed. This method of anesthesia is safe, effective, and well-tolerated by patients.


Development of food intake controls: neuroendocrine and environmental regulation of food intake during early life.
This article is part of a Special Issue "Energy Balance". The development of neuroendocrine regulation of food intake during early life has been shaped by natural selection to allow for optimal growth and development rates needed for survival. In vertebrates, neonates or early larval forms typically exhibit "feeding drive," characterized by a developmental delay in 1) responsiveness of the hypothalamus to satiety signals (e.g., leptin, melanocortins) and 2) sensitivity to environmental cues that suppress food intake. Homeostatic regulation of food intake develops once offspring transition to later life history stages when growth is slower, neuroendocrine systems are more mature, and appetite becomes more sensitive to environmental or social cues. Across vertebrate groups, there is a tremendous amount of developmental plasticity in both food intake regulation and stress responsiveness depending on the environmental conditions experienced during early life history stages or by pregnant/brooding mothers. This plasticity is mediated through the organizing effects of hormones acting on the food intake centers of the hypothalamus during development, which alter epigenetic expression of genes associated with ingestive behaviors. Research is still needed to reveal the mechanisms through which environmental conditions during development generate and maintain these epigenetic modifications within the lifespan or across generations. Furthermore, more research is needed to determine whether observed patterns of plasticity are adaptive or pathological. It is clear, however, that developmental programming of food intake has important effects on fitness, and therefore, has ecological and evolutionary implications.


A spectrocolorimetric study on the effect of ultraviolet irradiation of four tropical hardwoods.
Colour modifications caused by exposure to artificial UV radiation (350 nm, UV-A) of four tropical hardwoods, jatobá, angelim vermelho, garapeira, and marupá, have been evaluated by diffuse reflectance spectroscopy and by the CIE-L*a*b* system. To obtain the absorption maxima of the chromophore species formed during UV irradiation, Kubelka-Munk (K-M) difference spectra (non-irradiated-irradiated) have been recorded as a function of exposure time. The K-M difference spectra have shown that the investigated species develop strong absorption bands in the visible region upon UV irradiation that were assigned to the formation of lignin and extractive photodegradation products. The K-M difference spectra and CIE-L*a*b* parameters ( DeltaL, Deltaa, and Deltab) have shown that marupá is the wood species that suffers the major changes upon UV irradiation while angelim vermelho was the least affected.


Oxytocin ameliorates the immediate myocardial injury in rat heart transplant through downregulation of neutrophil-dependent myocardial apoptosis.
Cardiac oxytocin (OT) is structurally identical to that found in the hypothalamus, indicating that this active form of OT is derived from the same gene. The abundance of OT and its receptors in atrial myocytes suggests that, directly and/or via the release of the cardiac hormone atrial natriuretic peptide, this hormone regulates the force of cardiac contractions. Previous studies have demonstrated a role of OT in myocardial inflammatory responses. We sought to study protective myocardial and anti-inflammatory effects of OT in the immediate post-transplant period. We grouped adult male Albino rats into sham, control, and OT-treated groups. Control and treated groups underwent heterotopic cervical heart transplantation. Myocardial injury was assessed by measuring plasma cardiac troponin I, and myocardial proinflammatory cytokines as well as by performing histopathologic assessments injury score, and of apoptotic degree. Myocardial myeloperoxidase, neutrophil infiltration, neutrophil chemotactic mediators as well as formation of reactive oxygen and reactive nitrogen species were measured in the myocardium at 3 hours after reperfusion to assess neutrophil-dependent myocardial injury. OT downregulates neutrophil chemotactic molecules--KC/CXCL1 and MIP-2/CXCL2. The decrement in myocardial PMN infiltration was associated with reduced reactive oxygen and reactive nitrogen species formation in the myocardium at 3 hours after reperfusion following global ischemia. OT reduced postmyocardial ischemia/reperfusion apoptotic processed. OT ameliorated immediate myocardial injury in heart grafts, through downregulation of the inflammatory response, of reactive oxygen species, and of neutrophil dependent apoptosis.


Intracranial malignant cartilaginous tumours. Report of two cases and review of literature.
We report two cases of basicranial chondrosarcomas. Intracranial chondrosarcomas are particularly rare, amounting to 0.15% of all intracranial tumours. Their most frequent location is the skull base (76.19%), and more precisely the middle cranial fossa, as they arise from the spheno-occipital synchondrosis. Some intracerebral chondrosarcomas have also been reported. We also refer shortly to another kind of malignant cartilaginous neoplasm that was recently identified by Lichtenstein and Bernstein (1959). This is the mesenchymal chondrosarcoma. Fifteen cases of this have been reported.


Isolation and characterization of a siderophore-like growth factor from mutants of SV40-transformed cells adapted to picolinic acid.
We have isolated mutants of SV40-transformed BALB/3T3 cells adapted to grow in picolinic acid. A line of cells, derived from the mutant cells, that multiplies in the absence of serum has also been characterized. From ultrafiltrates of medium conditioned by contact with these cell lines, we have identified and partially purified a highly specific iron-binding ligand termed siderophore-like growth factor (SGF). Experiments have indicated that the factor is a peptide(s) of approximately 1600 daltons. In nanogram amounts, SGF solubilizes and binds Fe 3+ in vitro and stimulates the uptake of Fe 3+ in vivo. The Fe 3+ uptake preceded the stimulation of DNA synthesis induced by the factor in the mutant cell lines. The factor could not be separated into Fe 3+ binding and DNA synthetic activity, suggesting that the early iron uptake is an integral component of the proliferative response. These data support the hypothesis that SGF is representative of a family of mammalian siderophores which may have an important role in cell proliferation.


The role of coagulase-negative Staphylococcus in neonatal necrotizing enterocolitis.
Coagulase-negative Staphylococcus has emerged as a prominent pathogen in the neonatal intensive care unit and a recent report has implicated this organism in necrotizing enterocolitis (NEC). This same study suggests that Staphylococcus epidermidis is most commonly associated with a "mild form of enterocolitis." This prompted a review of the role of coagulase-negative Staphylococcus in the surgical complications of NEC. Between 1982 and 1986, 86 newborns underwent operation for perforation or intestinal necrosis secondary to NEC. Blood cultures, obtained within 72 hours of surgery, were positive in nine of 71 infants (13%). One third of these grew coagulase-negative Staphylococcus. Peritoneal cultures obtained at the time of operation were positive in 71 neonates. The incidence of Staphylococcus epidermidis was 30%. In a third of these cases, coagulase-negative Staphylococcus was the only organism covered. Overall mortality within the group was 33%. Coagulase-negative Staphylococcus was the single most frequent organism recovered from those infants who expired (35%). This data clearly indicates that Staphylococcus epidermidis must be considered as a significant pathogen in NEC. It is associated with both morbidity and mortality and, therefore, warrants appropriate aggressive therapy when recovered from the neonate with enterocolitis.