Plasma exchange in neurological diseases. A critical approach.
The rationale for and results of plasma exchange (PE) in the therapy of different immune-mediated neurological diseases such as myasthenia gravis, multiple sclerosis, acute and chronic-relapsing Guillain-Barré syndromes, polymyositis, dermatomyositis and amyotrophic lateral sclerosis are reviewed. Dialysis dementia and Refsum's disease, subacute sclerosing panencephalitis and schizophrenia are mentioned, too. If we exclude the treatment of acute Guillain-Barré syndrome, where PE alone appears to be sufficient to produce recovery or improvement, the combined use of immunosuppressive drugs and/or lymphocytapheresis is probably needed in the treatment of the other diseases. PE allows the disease to be controlled rapidly while long-term pharmacological control is established. An underlying theme in this review is the need of adequately controlled studies or at least of large case lists with exhaustive reports concerning both positive and negative results since a new perspective is needed for this topic. Nonetheless, a number of uncontrolled observations suggest that probably PE effectiveness in most immune-mediated neurological diseases could be proven if the requisite trials were performed.


Digoxin as an emerging therapy in noncardiac diseases.
The cardiac glycoside (CG) digoxin is a generic drug approved for the treatment of heart failure and supraventricular arrhythmias. Over the past few decades, substantial strides have been made toward repurposing digoxin to treat various noncardiac diseases. Here, we evaluate recent insights into basic and clinical work related to noncardiac use of digoxin.


The application of traditional transmission electron microscopy for autophagy research in Caenorhabditis elegans.
Traditional ultrastructural characterization of autophagic processes remains an important approach to be used in parallel with molecular genetics, light microscopy, and other methods. The special nature of Caenorhabditis elegans as an object for transmission electron microscopy makes its introduction into autophagy research a challenging task. The basis of the protocol to prepare C. elegans samples for autophagy studies was worked out around the turn of the millennium and has been used since then in my laboratory with some modifications. The method described here enables the user to prepare samples for systematic morphologic as well as morphometric investigations to characterize autophagy with a high but still realistic investment of effort.


Diosgenin improves vascular function by increasing aortic eNOS expression, normalize dyslipidemia and ACE activity in chronic renal failure rats.
In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress in the development of cardiovascular diseases has been highlighted. The aim of the present study is to evaluate the effect of diosgenin, an antioxidant on chronic renal failure (CRF) induced vascular dysfunction. CRF was induced by feeding the rats with a diet containing 0.75 % adenine and diosgenin was given orally (everyday at the dose of 40 mg/kg). Isometric force measurement was performed on isolated aortic rings in organ baths. Levels of reduced glutathione (GSH), nitric oxide metabolites, and endothelial nitric oxide synthase mRNA in rat aorta were examined. Further, plasma lipid profile, activity of enzymes of lipid metabolism, and aortic angiotensin converting enzyme (ACE) also studied. The overall results have proved that diosgenin attenuates CRF-induced impairment in acetylcholine induced endothelium-dependent and sodium nitroprusside induced endothelium-independent vascular relaxation. Moreover, it elevates the GSH and restores the eNOS mRNA expression level. CRF-induced dyslipidemia and ACE activity was also inhibited by diosgenin treatment. This study indicates that diosgenin have enough potential to protect vasculature against oxidative stress, dyslipidemia which in turn improves the vascular function in CRF milieu.


Lack of suppression by gangliosides of humoral or cellular immunity in vivo.
Gangliosides inhibit the proliferative responses of murine and human lymphocytes in vitro, and it has been suggested that they are immunosuppressive in vivo, although no in vivo studies have been performed. In view of the use of gangliosides to treat patients with a variety of neurological disorders, experiments were undertaken to evaluate the possible immunomodulatory effects of gangliosides in vivo. BALB/c mice were injected 5 days a week with buffer, mixed brain gangliosides, or GM1 ganglioside at dosage levels of 30 mg/kg, 60 mg/kg or 90 mg/kg. After 30 days of treatment, the mice were immunized with keyhole limpet hemocyanin or pneumococcal type III polysaccharide and the ganglioside treatment was continued. No differences between treated and control groups were noted in either the magnitude or duration of the antibody response. No differences between groups were noted in the proliferative responses of splenic mononuclear cells to concanavalin A or allogeneic antigens after 9-10 weeks of treatment, nor in the generation of cytotoxic effector cells after 90 days of treatment. Thus, despite the well-documented immunosuppressive effects of gangliosides in vitro, no evidence for a suppressive effect on humoral or cellular immunity in vivo was obtained in these studies.


Correction: Antiphospholipid Antibody and Risk of Retinal Vein Occlusion: A Systematic Review and Meta-Analysis.
[This corrects the article DOI: 10.1371/journal.pone.0122814.].


In situ regulation of selectivity and permeability by electrically tuning pore size in trans-membrane ion process.
Regulating ion transport behavior through pore size variation is greatly attractive for membrane to meet the need for precise separation, but fabricating nanofiltration (NF) membranes with tunable pore size remains a huge challenge. Herein, a NF membrane with electrically tunable pores was fabricated by intercalating polypyrrole into reduced graphene oxide interlayers. As the potential switches from reduction to oxidation, the membrane pore size shrinks by 11%, resulting in a 16.2% increase in salt rejection. The membrane pore size expands/contracts at redox potentials due to the polypyrrole volume swelling/shrinking caused by the insertion/desertion of cations, respectively. In terms of the inserted cation, Na+ and K+ induce larger pore-size stretching range for the membrane than Ca2+ due to greater binding energy and larger doping amount. Such an electrical response characteristic remained stable after multiple cycles and enabled application in ion selective separation; e.g., the Na+/Mg2+ separation factor in the reduced state is increased by 41% compared to that in the oxide state. This work provides electrically tunable nanochannels for high-precision separation applications such as valuable substance purification and resource recovery from wastewater.


Suspected survivor bias in case-control studies: stratify on survival time and use a negative control.
Selection bias in case-control studies occurs when control selection is inappropriate. However, selection bias due to improper case sampling is less well recognized. We describe how to recognize survivor bias (i.e., selection on exposed cases) and illustrate this with an example study. A case-control study was used to analyze the effect of statins on major bleedings during treatment with vitamin K antagonists. A total of 110 patients who experienced such bleedings were included 18-1,018 days after the bleeding complication and matched to 220 controls. A protective association of major bleeding for exposure to statins (odds ratio [OR]: 0.56; 95% confidence interval: 0.29-1.08) was found, which did not become stronger after adjustment for confounding factors. These observations lead us to suspect survivor bias. To identify this bias, results were stratified on time between bleeding event and inclusion, and repeated for a negative control (an exposure not related to survival): blood group non-O. The ORs for exposure to statins increased gradually to 1.37 with shorter time between outcome and inclusion, whereas ORs for the negative control remained constant, confirming our hypothesis. We recommend the presented method to check for overoptimistic results, that is, survivor bias in case-control studies.


Identification of Trypanosoma cruzi discrete typing units (DTUs) through the implementation of a high-resolution melting (HRM) genotyping assay.
Chagas disease, caused by Trypanosoma cruzi, is a geographically widespread anthropozoonosis that is considered a major public health problem in Latin America. Because this parasite presents high genetic variability, a nomenclature has been adopted to classify the parasite into six discrete typing units (DTUs): TcI, TcII, TcIII, TcIV, TcV, and TcVI, which present different eco-epidemiological, clinical, and geographic associations. Currently, the available genotyping methods present a series of drawbacks that implies the need for developing new methods for characterizing T. cruzi DTU's. The aim of this work was to genotype reference populations from T. cruzi by means of a High-Resolution Melting (HRM) genotyping assay. Amplification of the mini-exon gene allowed the genotyping of three distinct groups: TcI, TcII- TcIV- TcV, and TcIII-TcVI, while amplification of the 24sα gene generated non-overlapping melting temperature ranges for each DTU that were used to identify the groups in the six existing DTUs of Trypanosoma cruzi. The proposed genotyping assay allowed discrimination of the six genetic groups by obtaining specific melting curves for each DTU. The application of this technique is proposed because of its specificity, sensitivity, high performance, and low cost compared with other previously described characterization methods.


The temperature dependence of ultrasound-stimulated acoustic emission.
Given the high variability of tissue properties during sonication, temperature monitoring is one of the most crucial components for accurate thermal treatment of tissues with focused ultrasound and other thermotherapy devices. Recently, the method of ultrasound-stimulated acoustic emission (USAE) has been introduced as a potential method for measurements of mechanical properties of tissues. In this paper, the dependence of USAE on tissue temperature is determined. Because USAE depends on the acoustic and mechanical properties, both of which vary with temperature, it is hypothesized that the USAE signal is also temperature-dependent and in such a way that it can be used to guide thermal therapy. In a series of experiments, ex vivo porcine muscle and fat samples were exposed to ultrasound at power levels that induce temperature elevation. In both tissue types, below the coagulation threshold, the USAE amplitude was found to vary linearly with temperature. However, at higher powers, the correlation with temperature was lost due mainly to the irreversible nature of the changes in the tissue properties. Theoretical simulations were used to interpret the USAE response change with temperature involving both reversible and irreversible changes and during both heating and cooling. These results indicate that USAE may have important promise as a potential method for localizing temperature elevation and, thus, thermal surgery monitoring, as well as detection of irreversible changes in tissues.


Effect of different maize meal diets on growth and vitamin A: case-study on chickens.
South Africa embarked on mandatory vitamin and mineral fortification of wheat flour and maize meal in 2003 as part of a multi-faceted approach to alleviate malnutrition. However, it was reported, in 2008, that vitamin A deficiency increased despite the mandatory fortification programme. This motivates an investigation into the absorption of vitamin A as fortificant in the maize meal. Relative absorption, in chickens as the biological model, was determined by evaluating growth and vitamin A status. The weight, cumulative feed intake and liver retinol stores of chickens on different diets were measured over a 6week period. The fortified white maize meal diet was able to maintain the vitamin A status of the chickens. Poor absorption of the fortificant vitamin A is therefore not a constraint in combating vitamin A deficiency. It is in therefore also important to focus on the level of fortification delivered when consumed as a traditional prepared dish. In the traditional diet, maize porridge is often consumed with only a relish. The total fat content of the traditional meal is very low, lacking absorption enhancers.


Degradation and mineralization of the emerging pharmaceutical pollutant sildenafil by ozone and UV radiation using response surface methodology.
Pharmaceuticals and their degradation products which are present in wastewater and superficial waters are becoming an ecological issue. This research investigated the degradation and mineralization of synthetic solutions of the pharmaceutical compound sildenafil citrate (SC) by single ozonation and ozonation jointed with UV radiation (O3/UV). The effects of initial drug concentration (50-125 mg L-1), inlet ozone concentration (35-125 g Nm-3), and UV radiation on SC degradation and decrease of total organic carbon (TOC) were investigated using response surface methodology based on a central composite experimental design. Through the RSM analysis, it was possible to confirm the removal of SC for the entire experimental range. Major intermediates of SC degradation were identified and a degradation pathway was proposed. The kinetics of SC degradation was modeled as a pseudo-first-order reaction with a rate constant ranging between 0.072 and 1.250 min-1. The SC degradation and TOC removal were strongly enhanced by increasing the concentration of gaseous ozone at the inlet and incorporating UV radiation. The highest TOC removal reached at 60 min was 75%, in the O3/UV system, with initial SC content of 50 mg L-1 and inlet ozone concentration of 125 g Nm-3. The degradation rate of SC was increased 3 to 9 times in the presence of UV radiation. Ozone-based advanced oxidation processes appear as a suitable alternative for treatment of the emerging pollutant SC.


Smoking-related videos for use in cue-induced craving paradigms.
Environmental cues (e.g., the sight of a cigarette) have long been recognized as important triggers for craving in smokers. Available imaging technologies (e.g., fMRI) allow investigation of the neural mechanisms for cue-induced craving, but there stands a need for a cue-delivery system compatible with an MRI environment. We developed a standardized set of 24 high-resolution videos, 12 containing cigarette smoking scenes (e.g., lighting up), and 12 containing neutral scenes (e.g., reading a book), each 30 s long, with comparable lighting, visual complexity, and background filmed by a professional cinematographer. Study participants were 20 smokers (mean age=37.7 years, 50% female). Each was exposed to the 24 videos in a random order under laboratory conditions. Dependent measures included heart rate, blood pressure, skin conductance, skin temperature, and self-reported craving (0-100) following each video. Overall findings indicated that smokers had greater reactivity to the smoking videos than to neutral videos (p<.01). Follow-up univariate analyses revealed significant cue effects on self-reported craving, galvanic skin response, and skin temperature. Interestingly, exploratory examination of gender revealed that men had higher blood pressure and skin temperature responses than women, and that women had higher responses when viewing videos of women smoking than when viewing men smoking. Results support this set of videos as an effective tool for investigation of cue-elicited craving, and raise the possibility of unique gender effects in cue reactivity.


RubisCO selection using the vigorously aerobic and metabolically versatile bacterium Ralstonia eutropha.
Recapturing atmospheric CO2 is key to reducing global warming and increasing biological carbon availability. Ralstonia eutropha is a biotechnologically useful aerobic bacterium that uses the Calvin-Benson-Bassham (CBB) cycle and the enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) for CO2 utilization, suggesting that it may be a useful host to bioselect RubisCO molecules with improved CO2 -capture capabilities. A host strain of R. eutropha was constructed for this purpose after deleting endogenous genes encoding two related RubisCOs. This strain could be complemented for CO2 -dependent growth by introducing native or heterologous RubisCO genes. Mutagenesis and suppressor selection identified amino acid substitutions in a hydrophobic region that specifically influences RubisCO's interaction with its substrates, particularly O2 , which competes with CO2 at the active site. Unlike most RubisCOs, the R. eutropha enzyme has evolved to retain optimal CO2 -fixation rates in a fast-growing host, despite the presence of high levels of competing O2 . Yet its structure-function properties resemble those of several commonly found RubisCOs, including the higher plant enzymes, allowing strategies to engineer analogous enzymes. Because R. eutropha can be cultured rapidly under harsh environmental conditions (e.g., with toxic industrial flue gas), in the presence of near saturation levels of oxygen, artificial selection and directed evolution studies in this organism could potentially impact efforts toward improving RubisCO-dependent biological CO2 utilization in aerobic environments. d-ribulose 1,5-bisphosphate carboxylase/oxygenase, EC 18.104.22.168; phosphoribulokinase, EC 126.96.36.199.


Evaluation of US Hospital Episode Spending for Acute Inpatient Conditions After the Patient Protection and Affordable Care Act.
Under the Patient Protection and Affordable Care Act (ACA), US hospitals were exposed to a number of reforms intended to reduce spending, many of which, beginning in 2012, targeted acute care hospitals and often focused on specific diagnoses (eg, acute myocardial infarction, heart failure, and pneumonia) for Medicare patients. Other provisions enacted in the ACA and under budget sequestration (beginning in 2013) mandated Medicare fee cuts. To evaluate the association between the enactment of ACA reforms and 30-day price-standardized hospital episode spending. This policy evaluation included index discharges between January 1, 2008, and August 31, 2015, from a national random 20% sample of Medicare beneficiaries. Data analysis was performed from February 1, 2019 to July 8, 2020. Payment reforms after passage of the ACA. 30-day price-standardized episode payments. Three alternative estimation approaches were used to evaluate the association between reforms following the ACA and episode spending: (1) a difference-in-difference (DID) analysis among acute care hospitals, comparing spending for diagnoses commonly targeted by ACA programs with nontargeted diagnoses; (2) a DID analysis comparing acute care hospitals and critical access hospitals (not exposed to reforms); and (3) a generalized synthetic control analysis, comparing acute care and critical access hospitals. Supplemental analysis examined the degree to which Medicare fee cuts contributed to spending reductions. A total of 7 634 242 index discharges (4 525 630 [59.2%] female patients; mean [SD] age, 79.31 [8.02] years) were included. All 3 approaches found that reforms following the ACA were associated with a significant reduction in episode spending. The DID estimate comparing targeted and untargeted diagnoses suggested that reforms following the ACA were associated with a -$431 (95% CI, -$492 to -$369; -2.87%) change in total spending, while the generalized synthetic control analysis suggested that reforms were associated with a -$1232 (95% CI, -$1488 to -$965; -10.12%) change in total episode spending, amounting in a total annual savings of $5.68 billion. Cuts to Medicare fees accounted for most of these savings. In this policy evaluation, the ACA was associated with large reductions in US hospital episode spending.


From one year to the next: Video gaming life-style predicts subsequent psychosocial risk in adolescent boys and girls.
The ubiquitous societal presence of screens and gaming software is ever growing in popularity. However, can this recreational life-style pose risks for children's psychosocial adjustment? We thus examine associations between gaming life-style and later psychosocial development. The study sample originates from the 2120 boys and girls from the Quebec Longitudinal Study of Child Development birth cohort. At age 12, 625 boys and 702 girls from the original sample self-reported the number of hours engaged in video gaming per week and 1 year later, they self-reported psychosocial outcomes. Among boys, higher weekly video gaming frequency at age 12 forecasted increases in subsequent reactive aggression, emotional distress and ADHD symptoms at age 13. For girls, higher weekly video gaming frequency at age 12 predicted increases in subsequent reactive aggression and ADHD symptoms at age 13. No association between video game use and emotional distress was found for girls. In both boys and girls, a more intense video gaming life-style predicted subsequent risks for reactive aggression and ADHD symptoms, compared with their same sex counterparts reporting less intensity. For boys only, video gaming was associated with subsequent reactive emotional distress, likely due to the gender differences in violent content. Our data were collected at a time when there were less versatile screen-based technologies; therefore, our findings can be interpreted as very conservative compared to current estimates. Paediatric professionals and allied disciplines must take preventive measures to ensure that parents are aware of the risks associated with excessive use by their sons and daughters.


Periodontitis and diabetes mellitus co-morbidity: A molecular dialogue.
Type 2 diabetes mellitus (T2DM) and periodontitis are two biologically linked diseases that often coexist in complex interaction. While periodontitis may lead to insulin receptor desensitization, diabetes may increase the expression of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin 6 (IL-6), in the gingival crevicular fluid and activate osteoclasts via Receptor activator of nuclear factor kappa-Β ligand (RANK-L) production, leading to bone resorption. However, the association between the two diseases processes, where one may exacerbate the progression of the other, is unclear. In addition, both diseases have similar mechanistic themes, such as chronic inflammation and oxidative stress. This review aimed to investigate the pathophysiological and molecular mechanisms underlying T2DM and periodontitis. Uncontrolled diabetes is often associated with severe periodontitis, measured by clinical attachment loss. Alteration in the oral microbiome composition, which may activate the host inflammatory response and lead to irreversible oxidative stress, is a common finding in both diseases. An understanding of the molecular crosstalk between the two disease processes is crucial for developing therapeutic targets that inhibit bone resorption and halt the progression of periodontitis in patients with diabetes. The Oral microbiome composition in T2DM and periodontitis shifts toward dysbiosis, favoring bacterial pathogens, such as Fusobacteria and Porphyromonas species. Both conditions are marked by pro-inflammatory immune activity via the activation of Interleukin 17 (IL-17), Interleukin 1 (IL-1), TNF-α, and Nuclear Factor Kappa Beta (NF-κB). Common molecular crosstalk signaling appears to involve advanced glycation end products (AGEs) and oxidative stress. Thus, future drug targets are multifactorial, ranging from modulatory of host inflammatory response to preventing the accumulation of AGEs and oxidative free radicals.


Quality and Quantity in Kidney Cancer Surgery: The Role of Nonneoplastic Kidney and Kidney Volumetrics in Predicting Postoperative Renal Function.
To model renal function 2 years following radical nephrectomy with quantitative analyses using clinical, histopathologic, and renal composite cortical volumes (CCV). This retrospective study involved an assessment of the nonneoplastic kidney tissue by three blinded nephropathologists using modified Banff 1997 criteria for renal allograft pathology. Volumetric image acquisition was obtained by three independent radiologists using preoperative imaging. A 2-year estimated glomerular filtration (eGFR) calculator was created. Among the 126 patients, median age was 60 years; median CCV, 398.1 cm3; preoperative eGFR, 77 mL/min/1.73 m2; and 2-year postoperative eGFR, 54 mL/min/1.73 m2. Of the subjects, 64% had hypertension, 26% diabetes, and 37% were smokers. Increasing age, glomerulopathy/sclerosis, tubulointerstitial scarring, and arteriosclerosis were statistically significantly and adversely associated with eGFR. Conversely, increasing CCV was associated with a higher eGFR. Quantitative analysis of the nephrectomized kidney in conjunction with patient age can accurately predict renal function at 2 years.


The 'twinkle' artifact - A novel method of clip identification to facilitate targeted axillary surgery following neoadjuvant chemotherapy in breast cancer patients.
A targeted surgical approach which accurately determines axillary status after neoadjuvant chemotherapy (NAC) may allow appropriate de-escalation of surgical treatment. It is postulated that the combined use of a particular marker clip, ULTRACOR®TWIRL™ (Bard, Inc.), and specific ultrasound settings for its identification, may overcome the challenges of pre-operative localisation with size diminution of nodes following NAC. Hence, this feasibility study was performed. Three patients with locally advanced breast cancer (LABC), who had the Twirl marker clip placed in biopsy-proven metastatic axillary lymph nodes and completed treatment were included in this preliminary study. Preoperative sonographic identification of the clip and associated node was done on the day of surgery, confirmed by eliciting the 'twinkle' artifact, followed by hookwire localisation and resection. The 'twinkle' artifact was demonstrated within each specimen after resection. All three patients who completed treatment for LABC had successful identification and resection of clipped node aided by the 'twinkle artifact'. The 'twinkle' artifact is a novel and useful aid in identifying the Twirl™ clip marking a lymph node in the post-NAC setting, with the potential to be used intraoperatively.


The validity, reliability and feasibility of four instruments for assessing the consciousness of stroke patients in a neurological intensive care unit compared.
Early rehabilitation is the foundation for recovery for those admitted to an intensive care unit. Appropriate assessment of consciousness is needed before any rehabilitative intervention begins. This prospective study compared the validity, reliability and applicability of the sedation-agitation scale, the Richmond Agitation-Sedation Scale, the motor activity assessment scale and the Glasgow Coma Scale in a working neurological intensive care unit. Eighty-three stroke patients were assessed with the four scales by the same 3 raters acting independently: a senior physician, a senior therapist and a trainee. That generated 996 assessment records for comparison. Good agreement (r=0.98-0.99) was found among the sedation-agitation scale, the Richmond Agitation-Sedation Scale, the motor activity assessment scale scores, but the Glasgow Coma Scale ratings correlated less well (r=0.72-0.76) with the others. Consistent results were also found among the three raters. After stratification of the ratings by age, gender, level of consciousness and Acute Physiology and Chronic Health Evaluation score, the scales reported significant differences among the levels of consciousness and among those with different Acute Physiology and Chronic Health Evaluation results, but not with different age or gender strata. The four instruments tested are all reliable enough and feasible for use as a tool for consciousness screening in a neurological intensive care unit.


The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation.
SOX9 is responsible for campomelic dysplasia (CMPD). Symptoms of CMPD include recurrent apnea, upper respiratory infection, facial features, and shortening of the lower extremities. The variant acampomelic CMPD (ACMPD) lacks long bone curvature. A patient showed macrocephaly (+3.9 standard deviations [SD]) and minor anomalies, such as hypertelorism, palpebronasal fold, small mandible, and a cleft of soft palate without long bone curvature. From three months of age, he required tracheal intubation and artificial respiration under sedation because of tracheomalacia. Cranial magnetic resonance imaging was normal at one month of age but showed ventriculomegaly, hydrocephaly, and the corpus callosum thinning at two years of age. Exome sequencing revealed a de novo novel mutation, c. 236A>C, p (Q79P), in SOX9. Sox9 is thought to be crucial in neural stem cell development in the central and peripheral nervous system along with Sox8 and Sox10 in mice. In humans, neuronal abnormalities have been reported in cases of CMPD and ACMPD, including relative macrocephaly in 11 out of 22 and mild lateral ventriculomegaly in 2 out of 22 patients. We encountered a two-year old boy with ACMPD presenting with tracheomalacia and macrocephaly with a SOX9 mutation. We described for the first time an ACMPD patient with acquired diminished white matter and corpus callosal thinning, indicating the failure of oligodendrocyte/astrocyte development postnatally. This phenotype suggests that SOX9 plays a crucial role in human central nervous system development. Further cases are needed to clarify the relationship between human neural development and SOX9 mutations.


Mesentric lymphatic malformation presented with a small bowel internal hernia: A case report.
We report a case of a 2 years and 8 months boy presented with a small bowel obstruction occurring in a setting of mesenteric lymphatic malformation (LM). The case did not showed typical features of LM and thought to be a simple ascites. Nevertheless, the mass effect of the lesion was the salient finding and the case presented with a small bowel internal hernia which is a rare presentation. This emergent case was managed surgically.


Restoring black triangle with bioclear matrix versus conventional celluloid matrix method: a randomized clinical trial.
Open gingival embrasures form complex aesthetic and functional problems. This clinical trial assessed the bioclear matrix using injection molding technique against conventional celluloid matrix technique in management of black triangle. A total of 26 participants were randomly divided into two groups (13 participants each) according to the technique used. In group (A) celluloid conventional matrix method was used, while in group (B) bioclear matrix with injection molding technique was used. The different outcomes (Esthetic evaluation, marginal integrity and patient satisfaction) were evaluated following the FDI criteria by two blinded examiners. The evaluation was done at (T0) (immediate after restoration); (T6) after 6 months; and (T12) after 12 months. Statistical analysis was done as categorical and ordinal data were presented as frequency and percentage values. Categorical data were compared using fisher's exact test. Intergroup comparisons for ordinal data were analyzed utilizing the Mann-Whitney U test, while intragroup comparisons were analyzed using Friedman's test followed by the Nemenyi post hoc test. The significance level was set at p ≤ 0.05 within all tests. Regarding radiographic marginal integrity and marginal adaptation, the bioclear matrix group revealed superior results when compared to celluloid matrix group with a significant difference between both groups at all intervals (p < 0.05); however no significant difference was detected at different intervals. While for proximal anatomical form and esthetic anatomical form, as well as phonetics and food impaction, all cases in both groups were successful with no statistical significant difference between groups. For the periodontal response, there was no significant difference between groups. However, there was a significant difference between scores measured at different intervals, with T0 being significantly different from other intervals (p < 0.001). Marginal staining revealed that there was no significant difference between groups. While, a significant difference between scores measured at different intervals. The restorative management of the black triangle with both protocols was able to deliver superior aesthetic and good marginal adaptation; suitable biological properties; with adequate survival time. Both techniques were almost equally successful, however they are depending on the operator skills. The clinical trial was registered in the ( www. gov/ ) database in 23/07/2020; with the unique identification number NCT04482790.


Pneumocystis carinii: growth variables and estimates in the A549 and WI-38 VA13 human cell lines.
Recent studies indicate that rat Pneumocystis carinii can be propagated in the A549 cell line, an alveolar epithelioid cell line derived from human lung carcinoma. In the present study, growth of P. carinii was compared in the A549 cell line and the WI-38 VA13 subline 2RA, an SV40 transformed derivative of the human fetal fibroblast cell line with epithelioid morphology. Similar P. carinii growth occurred in both cell lines under optimal conditions, but the WI-38 VA13 cell line was usually more sensitive to changes in the culture system. Growth of P. carinii was affected by temperature, environmental gas mixture, motion of the cultures, and source and concentration of serum additives, but not by the presence of antibodies in the medium. A technique was developed for quantitating P. carinii in the lung inoculum which permitted analysis of P. carinii growth during the first 24 hr of culture. Inverted microscope and oil immersion phase-contrast microscopy were very helpful in monitoring the organism's stages of development and viability. Thus, this culture system should be helpful in establishing standard methodology for in vitro work with P. carinii.


The role of substrate feeding earthworms (Lumbricidae) for bioturbation in a beechwood soil.
Burrow formation (burrow length and faeces production) of the substrate feeding earthworm Aporrectodea caliginosa (Savigny) in relation to three temperatures (5, 10 and 15°C) and soil moisture contents (48, 60 and 73% water of dry wt) was determined. Soil moisture content affected the burrowing activity of A. caliginosa only below a distinct threshold (60% water of dry wt). At sufficient moisture an, increase in temperature by 5° C approximately doubled the amount of egesta produced. Another substrate feeding earthworm (Octolasion lacteum (Örley)) showed a similar pattern of burrowing activity.The data for the dependence of the faeces production of A. caliginosa on soil temperature and moisture content were combined with field data. The amount of faeces produced by the population of this earthworm species in a beechwood on limestone was calculated to be about 4.23 kg ha-1 a-1. The amount of egesta produced by all substrate feeding species is assumed to exceed 6 kg ha-1 a-1, which is equivalent to a soil layer of approximately 9 mm. This group of earthworms is therefore considered to be of greater importance for bioturbation and the formation of mull than previously assumed.


Post traumatic acquired multiple mesenteric defects.
Internal intestinal hernia has been defined as a bulging of the intestines through a normal or an abnormal peritoneal or mesenteric opening.(1) Internal hernias are a rare cause of small-bowel obstruction, with a reported incidence of 0.2-0.9%.(2) In this report, the patient presented with multiple episodes of intestinal obstruction. High index of suspicion aided the appropriate management of this case. An abdominal CT revealed signs of small bowel obstruction. With negative signs and symptoms indicating adhesions, malignancy or inflammatory causes, mesenteric defect was suspected. When the patient underwent laparotomy, multiple mesenteric defects were found. In the adult population, acquired mesenteric defects are more common than congenital defects. They can be caused by bowel surgery or abdominal trauma.(11) Patients with a history of blunt abdominal trauma may present with late complication caused by a missed diagnosis of an associated injury, such as bowel mesenteric injuries. In this case, the author describes a patient who developed multiple attacks of small bowel obstruction. He had no previous history of similar symptoms but did give a history of recent abdominal trauma managed conservatively. An abdominal CT was performed, and it showed signs of a mesenteric defect. In such a case, early operative intervention is essential to decrease morbidity and increase survival. (16) The diagnosis of post traumatic mesenteric injuries can be missed in conservatively managed trauma cases. For this reason, the decision of non-operative approach should be made following the exclusion of associated injuries.


[Suckling mortality in fattening rabbits in Switzerland].
The aims of this project were to determine mortality rate and aetiology of losses in suckling rabbits during the first 14 days of life. Post-mortem examinations were done on 1096 siblings from 8 conventional farms. Mortality rates varied from 0 to 17.0%. Main death causes were non-infectious and included stillbirth (13.9%), weakness due to reduced birth weight (3.0%), starvation (11.6%), runting (11.6%), cannibalism (0.5%) and scattering (7.9%). The last four causes mainly attributed to insufficient nursing by the doe. Only 21.8% of the losses were of infectious aetiology.


Aetiology of rheumatoid arthritis: an attempt to transmit an infective agent from patients with rheumatoid arthritis to baboons.
Thirty baboons were injected intravenously and intra-articularly with material from the joints of 19 patients with active rheumatoid arthritis or with control material. Fifteen of the 30 animals received synovial fluid cells or synovial membrane cells from 3 patients with seronegative arthritis. Ten animals received pooled cells from a total of 16 cases of seropositive arthritis. Five animals were given nonrheumatoid cells. No signs of arthritis were recognised in the 27 surviving animals during 3 years of observation. No significant biochemical, haematological, or serological changes occurred during this period, and no gross or microscopic evidence of synovial or systemic disease was found post mortem.


OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients.
It has been demonstrated that atherosclerosis (ATS) is enhanced in autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in SLE patients than in general population, they do not seem to fully explain the enhanced risk. ATS has the characteristics of an autoimmune chronic disease, involving both the innate and the adaptive immunity. Moreover, it satisfies the four criteria defining an autoimmune disease, proposed by Witebsky and Rose. It has been shown that some autoantibodies, including anti-oxLDL, anti-beta(2)GPI, anti-HSP60/65, and more recently anti-oxLDL/beta(2)GPI, play a key role in the pathogenesis of ATS. However the role of these autoantibodies in accelerated ATS in SLE patients is still controversial. In fact, some of them seem to be proatherogenic and other protective; moreover, it has been demonstrated that induced oral tolerance has a protective role against ATS. We have recently observed that the levels of oxLDL/beta(2)GPI antigenic complexes and their antibodies were higher in patients with SLE than in healthy subjects, but we did not find a clear association between oxLDL/beta(2)GPI complexes and IgG or IgM anti-oxLDL/beta(2)GPI autoantibodies and subclinical ATS in SLE patients. Many other studies are required to explain the role of autoantibodies in the pathogenesis of ATS in SLE patients, because the characteristics of SLE seem to mask their effects for atherogenesis.


A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia.
Several studies have documented the efficacy of amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia. Amphotericin, however, is a toxic drug. Fluconazole has broad-spectrum antifungal activity with an excellent safety profile. Although prophylactic use of fluconazole is widespread, its efficacy as an empiric antifungal agent has not been extensively investigated. We randomly assigned 106 patients with absolute neutropenia (< or = 500 cells microL) and persistent fever of undetermined origin (> 38 degrees C) despite 1 week of broad-spectrum antibiotic therapy to receive either fluconazole 400 mg orally daily or amphotericin B 0.5 mg/kg/day. Patients with obvious invasive fungal infections were excluded, as were those with abnormal renal or hepatic function. Success was defined as defervescence with the initially assigned antifungal regimen without development of clinically evident invasive fungal infection. Six patients were excluded from the analysis, mostly because they did not have severe neutropenia. Forty-eight patients received amphotericin B, and 52 received fluconazole. Baseline clinical characteristics and laboratory parameters as well as duration of neutropenia (7.7 versus 6.9 days), duration of fever (7.8 versus 8.1 days), and duration of hospitalization (10.4 versus 8.3 days) were similar between those receiving amphotericin and fluconazole. Treatment success rates and mortality rates were similar in the two groups: 22 (46%) patients in the amphotericin group and 29 (56%) patients in the fluconazole group responded successfully to therapy (P = 0.3), whereas 16 (33%) patients in the amphotericin group and 14 (27%) patients in the fluconazole group died during hospitalization (P = 0.5). Adverse events such as chills and fever (4 versus 1), bronchospasm (2 versus none), severe hypokalemia (25 versus 12) and nephrotoxicity (9 versus 3) were more frequently observed in patients receiving amphotericin. Adverse prognostic factors included prolonged duration of neutropenia and pneumonia. These results suggest that fluconazole is an equally effective but less toxic alternative to amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia.


[Network activity of "interneurons" and large cells of amygdala in active and passive rabbits].
By plotting cross-correlation histograms differences were found in interaction of conjectural small "interneurons" and large principal cells of the central and basal amygdalar nuclei in negative emotional situations. The network activity of "nterneurons" was higher than in principal cells. "Interneurons" more frequently had excitatory and inhibitory input or output connections with neighbouring cells, latency of their connections with other cells was smaller than in principal neurons. Interaction of "interneurons" and principal cells differed in animals with active and passive behavioural strategy in negative emotional situations. As compared to active animals, in passive rabbits inhibitory connections to "interneurons" from other cells occurred more frequently, excitatory or inhibitory connections from "interneurons" to principal cells appeared more rare.


A miniaturized hydrogel-based in vitro model for dynamic culturing of human cells overexpressing beta-amyloid precursor protein.
Recent findings have highlighted an interconnection between intestinal microbiota and the brain, referred to as microbiota-gut-brain axis, and suggested that alterations in microbiota composition might affect brain functioning, also in Alzheimer's disease. To investigate microbiota-gut-brain axis biochemical pathways, in this work we developed an innovative device to be used as modular unit in an engineered multi-organ-on-a-chip platform recapitulating in vitro the main players of the microbiota-gut-brain axis, and an innovative three-dimensional model of brain cells based on collagen/hyaluronic acid or collagen/poly(ethylene glycol) semi-interpenetrating polymer networks and β-amyloid precursor protein-Swedish mutant-expressing H4 cells, to simulate the pathological scenario of Alzheimer's disease. We set up the culturing conditions, assessed cell response, scaled down the three-dimensional models to be hosted in the organ-on-a-chip device, and cultured them both in static and in dynamic conditions. The results suggest that the device and three-dimensional models are exploitable for advanced engineered models representing brain features also in Alzheimer's disease scenario.


Interaction of the CDK2-associated protein-1, p12(DOC-1/CDK2AP1), with its homolog, p14(DOC-1R).
Human DOC-1/CDK2AP1 gene encodes a growth suppressor protein of 12kDa (p12(DOC-1/CDK2AP1)). Recently, p12(DOC-1/CDK2AP1) has been shown to associate with cell cycle proteins including CDK2 and DNA polymerase alpha/primase. It negatively regulates CDK2 activities and suppresses DNA replication. Therefore, identification of other p12(DOC-1/CDK2AP1) interacting proteins might clarify its role in the cell cycle regulation and carcinogenesis. The purpose of this study was to identify additional p12(DOC-1/CDK2AP1) interacting proteins using the yeast two-hybrid system. Using human p12(DOC-1/CDK2AP1) as a bait in a liver cDNA library screening, cDNA clones identical to human DOC-1R transcript were identified. The interaction between p12(DOC-1/CDK2AP1) and p14(DOC-1R) was verified in vitro and in cells. GST pull-down assay and immunoprecipitation experiments confirmed the interaction between the two proteins. The critical region for p12(DOC-1/CDK2AP1)'s interaction with p14(DOC-1R) was defined to amino acids 20-25 by using a series of deletion mutants as baits in the yeast two-hybrid system. Our data indicated that p12(DOC-1/CDK2AP1) could associate with its homologous protein, p14(DOC-1R).


Physiological status and anatomical severity factors associated with child versus adult bicyclist fatalities based on a national trauma dataset.
Bicyclists still account for the majority of child deaths in traffic accidents, despite a gradual decrease in incidence. Therefore, we investigated factors associated with child and adult bicyclist fatalities. In this retrospective study, we used data from a national hospital-based database, the Japan Trauma Data Bank. Data from 2004 to 2019 were obtained for child cyclists (5-18 years; n = 4832) and adult cyclists (26-45 years; n = 3449). In each age group, physiological variables, outcomes, and injury severity were compared between fatal and non-fatal cases. Multivariate logistic regression was performed to determine factors associated with fatality. In adults, fatality was associated with lower values for body temperature, Glasgow Coma Scale score, and Abbreviated Injury Scale (AIS) score for the neck and upper extremities, and with higher values for respiratory rate, heart rate, focused assessment with sonography for trauma positivity rate, and AIS scores for the head, chest, and abdomen. In children, fatality was associated with lower values for body temperature and the Glasgow Coma Scale score, and with higher values for the AIS chest score. These findings point to factors associated with bicyclist fatalities and may help in the development of effective strategies to reduce these fatalities.


Dependent layering of contrast medium in cystic astrocytomas.
Dependent layering of contrast enhanced fluid in cystic astrocytomas has not been described on computed tomograms. Two children in which this phenomenon occurred are described and its significance is discussed. In a third cystic lesion contrast layering was confirmed by head tilting.


Acute anterior compartmental syndrome of the thigh following contusion. A case report and review of the literature.
Contusion is a rare cause of acute compartmental syndrome in the thigh. To date, no case report has described blunt trauma precipitating this limb-threatening condition. The patient in this case report developed rapidly progressive signs and symptoms which required emergency fasciotomy. Delayed primary closure was possible and recovery was complete. The etiologies, diagnosis and management of thigh compartmental syndrome are reviewed.


Visible Light-Induced Direct S0 → Tn Transition of Benzophenone Promotes C(sp3)-H Alkynylation of Ethers and Amides.
Benzophenone has an S0 → S1 absorption band at 365 nm. However, the rarely reported S0 → Tn transition occurs upon irradiation at longer wavelengths. Herein, we employed benzophenone as a catalyst and exploited its S0 → Tn transition in C(sp3)-H alkynylations with hypervalent iodine reagents. The selective benzophenone excitation prevented alkynylating reagent decomposition, enabling the reaction to proceed under mild conditions. The reaction mechanism was investigated by spectroscopic and computational studies.


The association of HDL-apoCIII with coronary heart disease and the effect of statin treatment on it.
Apolipoprotein CIII (apoCIII) is considered to impair the anti-atherogenic effect of high density lipoprotein (HDL) in coronary heart disease (CHD) patients, and apoCIII content in HDL (HDL-apoCIII) predicts CHD more accurately. However, the relationship between HDL-apoCIII and CHD, and the effect of statin treatment on HDL-apoCIII are still unclear. The aims of the study are to establish the association of HDL-apoCIII with CHD, and investigate the effect of statin treatment on HDL-apoCIII in CHD patients. We conducted a hospital-based observational study. Totally 80 non-CHD patients and 120 CHD patients without statin treatment were previously enrolled in this study. All the CHD patients received statin treatment, and 63 of them were followed after 3 months of regular statin treatment. HDL sample of each patient was isolated by density gradient ultracentrifugation from fasting venous plasma, and HDL-apoCIII of each patient was measured by ELISA method. HDL-apoCIII was significantly higher in CHD patients than non-CHD patients (p < 0.05), and it was still an independent predictor of CHD after adjusting for other factors. Total plasma apoCIII, especially HDL-apoCIII was significantly elevated after statin treatment in CHD patients, whereas total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and apolipoprotein B (apoB) were decreased significantly (p < 0.05). Compared with CHD patients without diabetes mellitus (DM), the effect of statin treatment on apoCIII markers was minor in CHD patients with DM. And HDL-apoCIII correlated with plasma TG significantly in non-CHD and CHD patients (p < 0.05), but the correlation in CHD patients did not exist after statin treatment (p > 0.05). HDL-apoCIII has a significant and positive association with CHD. Although conventional atherogenic lipid markers have a significantly decrease in CHD patients after statin treatment, HDL-apoCIII has a further elevation at the same time.


Contribution of trehalose to ethanol stress tolerance of Wickerhamomyces anomalus.
The ascomycetous heterothallic yeast Wickerhamomyces anomalus (WA) has received considerable attention and has been widely reported in the winemaking industry for its distinctive physiological traits and metabolic attributes. An increased concentration of ethanol during ethanol fermentation, however, causes ethanol stress (ES) on the yeast cells. Trehalose has been implicated in improving survival under various stress conditions in microorganisms. Herein, we determined the effects of trehalose supplementation on the survival, differentially expressed genes (DEGs), cellular morphology, and oxidative stress tolerance of WA in response to ES. The results indicated that trehalose improved the survival and anomalous surface and ultrastructural morphology of WA. Additionally, trehalose improved redox homeostasis by reducing the levels of reactive oxygen species (ROS) and inducing the activities of antioxidant enzymes. In addition, DEGs affected by the application of trehalose were enriched in these categories including in gene expression, protein synthesis, energy metabolism, and cell cycle pathways. Additionally, trehalose increased the content of intracellular malondialdehyde (MDA) and adenosine triphosphate. These results reveal the protective role of trehalose in ES mitigation and strengthen the possible uses of WA in the wine fermentation sector.


Fat Grafting for Facial Rejuvenation through Injectable Tissue Replacement and Regeneration: A Differential, Standardized, Anatomic Approach.
Injectable tissue replacement and regeneration (ITR2) is a standardized fat grafting technique, which anatomically addresses losses of facial volume, laxity, and sun damage of the skin resulting from the natural processes of aging. Based on the structural differences of fat existing in the deeper versus the superficial fat compartments of the face, while accounting for skeletal losses and skin aging, ITR2 utilizes 3 sizes of fat grafts-millifat (parcel size 2.0-2.5 mm), microfat (1.0 mm), and nanofat (<500 μm)-to replicate characteristics of fat cells lost with facial decay and provide increased blood supply and improvements in aging skin.


The evolution of functional complexity within the β-amylase gene family in land plants.
β-Amylases (BAMs) are a multigene family of glucan hydrolytic enzymes playing a key role not only for plant biology but also for many industrial applications, such as the malting process in the brewing and distilling industries. BAMs have been extensively studied in Arabidopsis thaliana where they show a surprising level of complexity in terms of specialization within the different isoforms as well as regulatory functions played by at least three catalytically inactive members. Despite the importance of BAMs and the fact that multiple BAM proteins are also present in other angiosperms, little is known about their phylogenetic history or functional relationship. Here, we examined 961 β-amylase sequences from 136 different algae and land plant species, including 66 sequenced genomes and many transcriptomes. The extraordinary number and the diversity of organisms examined allowed us to reconstruct the main patterns of β-amylase evolution in land plants. We identified eight distinct clades in angiosperms, which results from extensive gene duplications and sub- or neo-functionalization. We discovered a novel clade of BAM, absent in Arabidopsis, which we called BAM10. BAM10 emerged before the radiation of seed plants and has the feature of an inactive enzyme. Furthermore, we report that BAM4 - an important protein regulating Arabidopsis starch metabolism - is absent in many relevant starch-accumulating crop species, suggesting that starch degradation may be differently regulated between species. BAM proteins originated sometime more than 400 million years ago and expanded together with the differentiation of plants into organisms of increasing complexity. Our phylogenetic analyses provide essential insights for future functional studies of this important class of storage glucan hydrolases and regulatory proteins.


Massive transfusion.
Massive transfusion is a potentially serious problem associated with a number of complications, including changes in coagulation factor and platelet concentration, nonmechanical bleeding, hypothermia, pulmonary dysfunction, hypokalemia and hyperkalemia, hypocalcemia, hypomagnesemia, acidosis and alkalosis, immune suppression, blood transfusion reactions, and transmission of infectious diseases. The pathophysiology and management of massive transfusion are reviewed in this article.


Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation.
Differentiating cells undergo programmed alterations in their patterns of gene expression, which are often regulated by structural changes in chromatin. Here we demonstrate that T cell differentiation results in long-range changes in the chromatin structure of effector cytokine genes, which persist in resting Th1 and Th2 cells in the absence of further stimulation. Differentiation of naive T helper cells into mature Th2 cells is associated with chromatin remodeling of the IL-4 and IL-13 genes, whereas differentiation into Th1 cells evokes remodeling of the IFNgamma but not IL-4 or IL-13 genes. IL-4 locus remodeling is accompanied by demethylation and requires both antigen stimulation and STAT6 activation. We propose that chromatin remodeling of cytokine gene loci is functionally associated with productive T cell differentiation and may explain the coordinate regulation of Th2 cytokine genes.


Fused aminotetralins: novel antagonists with high selectivity for the dopamine D3 receptor.
Starting from a series of 2-aminotetralins 1, a novel series of N-[4-(4-phenylbenzoylamino)butyl]-octahydrobenzoquinolines and hexahydrobenzoindoles with high potency and selectivity for the dopamine D3 receptor has been designed. The effect of ligand chirality on binding affinity has been established. Selected derivatives (e.g. 2o, 2p) show high functional selectivity and enhanced in vivo properties compared to 1.


Update on Investigation Methods for Lower Extremity Biomechanics.
Imaging with biomechanical analysis augments the clinical examination and improves outcomes by correlating imaging findings with the examination. Plain film radiographs are the gold standard to assess osseous alignment. The biomechanical examination provides information to formulate an accurate assessment. Weightbearing computed tomography scanning is a potentially valuable for functional information about joint biomechanics. True alignment of the lower extremity can be appreciated on weightbearing computed tomography scanning. Soft tissue structures can be assessed with diagnostic ultrasound examination. Acute and chronic injuries that compromise joint stability can be identified.


Frequency controlled agglomeration of pt-nanoparticles in sonochemical synthesis.
Optimizing the surface area of nanoparticles is key to achieving high catalytic activities for electrochemical energy conversion devices. In this work, the frequency range (200 kHz-500 kHz) for maximum sonochemical radical formation was investigated for the sonochemical synthesis of Pt-nanoparticles to assess whether an optimum frequency exists or if the entire range provides reproducible particle properties. Through physical and electrochemical characterization, it was found that the frequency dependent mechanical effects of ultrasound resulted in smaller, more open agglomerates at lower frequencies with agglomerate sizes of (238 ± 4) nm at 210 kHz compared to (274 ± 2) nm at 326 kHz, and electrochemical surface areas of (12.4 ± 0.9) m2g-1 at 210 kHz compared to (3.4 ± 0.5) m2g-1 at 326 kHz. However, the primary particle size (2.1 nm) and the catalytic activity towards hydrogen evolution, (19 ± 2) mV at 10mA cm2,remained unchanged over the entire frequency range. Highly reproducible Pt-nanoparticles are therefore easily attainable within a broad range of ultrasonic frequencies for the sonochemical synthesis route.


Predicting the outcome of distal radius fractures.
There are myriad factors that affect patient satisfaction following a distal radius fracture, including anatomic alignment, age, motion, pain,and hand dominance to name a few. The seeming contradictions in the literature serve to illustrate that individual outcomes are not entirely predict-able because of the different functional demands,expectations, and pain tolerance for each patient. Elderly populations may tolerate greater degrees of residual deformity because of a more sedentary lifestyle. Unrecognized intracarpal pathology may account for poor results despite acceptable radiographic alignment. Possessing a knowledge of the predictive factors that affect adversely the functional outcome, however, does allow the surgeon to manage complications proactively to maximize the potential for an acceptable end result.


Respiratory failure from severe organophosphate toxicity due to absorption through the skin.
Organophosphates are the most common group of chemicals involved in poisoning in Sri Lanka. Usually, poisoning is by ingestion for suicidal purposes, although accidental poisoning is not uncommon. Poisoning due to absorption through intact or damaged skin is rare. A 32-year-old man was admitted to a peripheral hospital following assault with a 100-ml bottle of insecticide called Monocrotophos, an organophosphate. He had a 2-in. long laceration just above his left eyebrow and there was spilling of the liquid contained in the bottle over his head and face. The liquid was wiped off but the head or face was not washed. After about 3 h the patient developed symptoms and signs of early organophosphate poisoning which were treated with atropine and pralidoxime. On the 3rd day, while on therapy, the patient developed severe weakness of limbs and respiratory distress needing intubation and assisted ventilation. The patient was transferred to the neurology intensive care unit of the General Hospital, Colombo, on the eighth day. His serum potassium levels were low and an ECG showed prominent U waves in all leads. The plasma cholinesterase levels were within 37.5-50% of normal even on the 20th day indicating severe exposure.


Influence of food adhesivity and quantity in lip closing pressure.
Lip closing is an important motor act in food acquisition. Appropriate food capture in anticipatory and early oral stages of feeding is essential for mastication and swallowing. The aim of this study was to investigate the effect of food type and quantity on lip closing pressure during food capture with a spoon, and to identify normal lip function during food acquisition in healthy young adults. Twenty young healthy males (age range: 22-30 years) participated in this study. They were asked to eat the test food freely with a spoon. Test foods were yogurt and cream cheese, which were given in quantities of 3, 5 and 10 g in weight; 3 ml water was included as a reference. A strain gauge transducer was embedded in the spoon in advance, and lip closing pressures during food capture were measured and recorded. The Vicon motion analysis system was used to collect three-dimensional kinematic data of spoon operation. Positive pressure with lip closing during capture of adhesive food, such as cream cheese, significantly increased (P < 0.001). Moreover, positive pressure significantly decreased when food quantity increased (P < 0.01), irrespective of food type. Negative pressure that preceded positive pressure appeared more frequently during cream cheese intake and increased when food quantity on the spoon increased (P < 0.001). These findings indicated that participants sucked or squeezed the spoon further during capture of adhesive food. Maximum mouth opening occurred predominantly during the spoon insertion period, while mouth closing occurred predominantly during the spoon withdrawal period. After mouth closing, all subsequent lip pressure events appeared in the withdrawal period. Our results may be useful for comprehending normal lip function during food acquisition in healthy young adults. They may also aid in the diagnosis and management of abnormal lip function in oral hypofunction and dysfunction, which can be examined in future studies.


Clinical survival of No-prep indirect composite laminate veneers: a 7-year prospective case series study.
The no preparation technique which is a reversible form of treatment characterized by the absence of tooth tissue preparation and preserves the soft tissue architecture while preserving all natural tooth structures is indicated in cases where the tooth structure allows material to be added. The aim of this study is to evaluate the clinical performance and survival rates of indirect composite laminate veneers with no preparation after 7 years. A total of 80 indirect composite veneers were placed on maxillary anterior teeth in 35 patients (n = 80). Diastema (n = 64), wedge tooth anomalies (n = 9) and re-shaping (n = 7) were the main indications for veneer treatments. All laminate veneers were fabricated with an indirect microhybrid composite material (Gradia, GC Dental). No tooth preparation was performed. Light-cured resin cement (Choice 2, Bisco) was used to lute the veneers. Composite veneers were evaluated using Modified United States Public Health Service criteria. Survival rates of the veneers were calculated using Kaplan-Meier statistics. The data containing the results of the USPHS criteria at baseline, 2 years and 7 years was statistically analyzed using Wilcoxon Signed Rank test at the 0.05 level of significance. The overall survival rate was 91.3%. After 7 years, 7 absolute failures including 4 debonding (marginal adaptation, score 4) and 3 fractures (fracture of restoration, score 3) were noted. Color match was scored as 1 (n = 34) and 2 (n = 15). Slightly rough surfaces (41 of 73 laminates) and slight marginal discoloration (15 of 73 laminates) were noted. The overall scores after 84 months were significantly higher than the baseline scores for the marginal adaptation (p = 0.008), color match (p = 0.000), marginal discoloration (p = 0.000), surface roughness (p = 0.000), and fracture of restoration (p = 0.001) criteria. In this study, indirect composite veneers without any preparation on maxillary anterior teeth showed acceptable performance in terms of both survival rate and quality of restorations. This procedure offers a predictable and successful treatment that ensures maximum preservation of the intact tooth.


Validation of content and structure of the Return-to-work assessment for post-stroke survivors.
Validation of an instrument consist of three main types: content, criterion and construct. Content validity needs to be determined in order for an instrument to be acceptable for use, validity establishes the fact that an instrument measures exactly what it proposes to measure. The Return-to-work assessment scale (RAS) was developed to measure three aspects of return to work: (Personal factors and/or issues, work issues and contextual factors) in 2021. To report on the processes followed in establishing the face and content validity of the RAS. Twenty participants took part in our study, they were selected purposively and conveniently from a pool of professionals and post stroke survivors. The Delphi survey technique was used to arrive at consensus and professional opinion on the items included in the RAS. Consensus was sought on the items, domains and subdomains included in the RAS that was used to assess return-to-work after a stroke. Our study was concluded after the third round. One item was remove out of the original 86, three (3) domains made up of eleven (11) subdomains were retained. The RAS had consensus of 100% after three rounds of scrutiny for all items. The RAS was found to be valid, thereby establishing its face and content validity. The RAS is valid and was recommended for psychometric testing which was the next stage after face and content validity.


Experimental induction of middle ear cholesteatoma in rats.
We induced cholesteatoma in two groups of rats by instilling different concentrations of propylene glycol into the middle ear cavity. Fifteen rats were exposed to 50% propylene glycol (group I), while pure propylene glycol was applied to six others (group II). The group I rats were killed 1 month after instillation. Seven of the 15 showed cholesteatoma in the middle ear with accumulation of keratin debris. The group II rats were killed 3 months after instillation. All six animals showed inflammation in the experimental ears, and five of the six experimental ears showed cholesteatoma in the middle ear cavity. Six experimental ears in group I and five in group II revealed retraction of the tympanic membrane, possibly due to eustachian tube obstruction. Bone resorption was seen along with cholesteatoma and inflammatory cells and osteoclasts in the middle ear of all 11 of these rats. The seventh cholesteatoma of group I can be classified as a microcholesteatoma, a pearl-like cyst within the tympanic membrane. The microcholesteatoma was formed by an invasion of basal cells from the tympanic epidermis and the proliferation of these cells in the fibrous layer of the tympanic membrane. Our findings suggest that cholesteatoma in the middle ear cavity is a response to the inflammation produced by high concentrations of propyleme glycol.


Why we need to abandon fixed cutoffs for goodness-of-fit indices: An extensive simulation and possible solutions.
To evaluate model fit in confirmatory factor analysis, researchers compare goodness-of-fit indices (GOFs) against fixed cutoff values (e.g., CFI > .950) derived from simulation studies. Methodologists have cautioned that cutoffs for GOFs are only valid for settings similar to the simulation scenarios from which cutoffs originated. Despite these warnings, fixed cutoffs for popular GOFs (i.e., χ2, χ2/df, CFI, RMSEA, SRMR) continue to be widely used in applied research. We (1) argue that the practice of using fixed cutoffs needs to be abandoned and (2) review time-honored and emerging alternatives to fixed cutoffs. We first present the most in-depth simulation study to date on the sensitivity of GOFs to model misspecification (i.e., misspecified factor dimensionality and unmodeled cross-loadings) and their susceptibility to further data and analysis characteristics (i.e., estimator, number of indicators, number and distribution of response options, loading magnitude, sample size, and factor correlation). We included all characteristics identified as influential in previous studies. Our simulation enabled us to replicate well-known influences on GOFs and establish hitherto unknown or underappreciated ones. In particular, the magnitude of the factor correlation turned out to moderate the effects of several characteristics on GOFs. Second, to address these problems, we discuss several strategies for assessing model fit that take the dependency of GOFs on the modeling context into account. We highlight tailored (or "dynamic") cutoffs as a way forward. We provide convenient tables with scenario-specific cutoffs as well as regression formulae to predict cutoffs tailored to the empirical setting of interest.


Changes in biophysical characteristics of PFN1 due to mutation causing amyotrophic lateral sclerosis.
Single amino acid mutations in profilin 1 (PFN1) have been found to cause amyotrophic lateral sclerosis (ALS). Recently, we developed a mouse model for ALS using a PFN1 mutation (glycine 118 to valine, G118V), and we are now interested in understanding how PFN1 becomes toxically lethal with only one amino acid substitution. Therefore, we studied mutation-related changes in the PFN1 protein and hypothesized that such changes significantly disturb its structure. Initially, we expressed and studied the purified PFN1WT and PFN1G118V proteins from bacterial culture. We found that the PFN1G118V protein has a different mean residue ellipticity, as measured by far-UV circular dichroism, accompanied by a spectral shift. The intrinsic fluorescence of PFN1G118V showed a small fluctuation in maximum fluorescence absorption and intensity. Moreover, we examined the time course of PFN1 aggregation using SDS-PAGE, western blotting, and MALDI-TOF/TOF and found that compared with PFN1WT, PFN1G118V had an increased tendency to form aggregates. Dynamic light scattering data confirmed this, showing a larger size distribution for PFN1G118V. Our data explain why PFN1G118V tends to aggregate, a phenotype that may be the basis for its neurotoxicity.


Coronary reactive hyperaemia and coronary dilator action of adenosine during intracoronary infusion of angiotensin II.
Investigations were carried out in chloralose-anesthetized, thoracotomized dogs. The effects of an intracoronary infusion of angiotensin II (3 ng/ml coronary blood) on reactive hyperaemic blood flow and adenosine-induced coronary vasodilation were established. Coronary artery occlusions were performed over periods of 5, 10 and 25 heart beats and adenosine was injected intracoronarily at dosages of 2, 4, and 8 microgram/kg body weight. The vasodilator effect of adenosine and reactive hyperaemia after 10 and 25 heart beats were both significantly diminished by angiotensin II. By contrast, reactive hyperaemia after coronary artery occlusion lasting 5 heart beats remained unchanged. The present results obtained with angiotensin II further confirm that adenosine is only partially involved in mediating reactive hyperaemia and that this involvement takes place only after sufficiently long periods of coronary artery occlusion.


TAVR - From inoperable to younger, lower-risk patients: A slippery slope?
Despite current valve guidelines recommending both transcatheter and surgical aortic valve replacement (TAVR and SAVR, respectively) in patients with symptomatic severe aortic stenosis (AS), TAVR has recently become the preferred treatment over SAVR, driven by its minimal invasiveness, faster recovery and earlier improvement in quality of life. However, several limitations and unresolved issues remain with TAVR, including stroke, conduction system disorder, durability, bicuspid anatomy, coronary reaccess and lifetime management with aortic valve reintervention. Our review aims to highlight the above issues and discuss them in depth, to demonstrate the complementary role of TAVR and SAVR in the treatment of AS.


KIF2C accelerates the development of non-small cell lung cancer and is suppressed by miR-186-3p via the AKT-GSK3β-β-catenin pathway.
This study aimed to explore how kinesin family member 2C (KIF2C) influences the progression of non-small cell lung cancer (NSCLC). The levels of KIF2C and microRNA-186-3p (miR-186-3p) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Through the utilization of cell counting kit-8 (CCK-8) assay, colony formation assay, wound closure assay, and Transwell assay, NSCLC cell proliferation, migration, and invasion were identified, respectively. NSCLC cell apoptosis was assessed using the TUNEL assay and flow cytometry (FCM) assay. Luciferase reporter analysis was used to investigate the relationship between KIF2C and miR-186-3p. Western blot assays were conducted to investigate the influence of KIF2C on the AKT-GSK3β-β-catenin pathway. The results showed that KIF2C was up-regulated in NSCLC cells, which predicted poor prognosis. KIF2C overexpression promoted the proliferation, migration, and invasion of NSCLC cells as well as inhibited NSCLC cell apoptosis. KIF2C was as a key target of miR-186-3p. High expression of KIF2C, meanwhile, increased the levels of β-catenin, p-GSK-3β and phosphorylated protein kinase B (p-AKT). KIF2C downregulation and miR-186-3p upregulation reversed these outcomes. As an oncogenic factor, KIF2C is negatively regulated by miR-186-3p and participates in the progression of NSCLC through the AKT-GSK3β-β-catenin pathway.


Determination of the binding properties of the uremic toxin phenylacetic acid to human serum albumin.
Uremic toxins are compounds normally excreted in urine that accumulate in patients with chronic kidney disease as a result of decreased renal clearance. Phenylacetic acid (PAA) has been identified as a new protein bound uremic toxin. The purpose of this study was to investigate in vitro the interaction between PAA and human serum albumin (HSA) at physiological and pathological concentrations. We used ultrafiltration to show that there is a single high-affinity binding site for PAA on HSA, with a binding constant on the order of 3.4 × 10(4) M(-1) and a maximal stoichiometry of 1.61 mol per mole. The PAA, at the concentration reported in end-stage renal patients, was 26% bound to albumin. Fluorescent probe competition experiments demonstrated that PAA did not bind to Sudlow's site I (in subdomain IIA) and only weakly bind to Sudlow's site II (in subdomain IIIA). The PAA showed no competition with other protein-bound uremic toxins such as p-cresyl-sulfate or indoxyl sulfate for binding to serum albumin. Our results provide evidence that human serum albumin can act as carrier protein for phenylacetic acid.


Both standing and postural threat decrease Achilles' tendon reflex inhibition from tendon electrical stimulation.
Golgi tendon organs (GTOs) and associated Ib reflexes contribute to standing balance, but the potential impacts of threats to standing balance on Ib reflexes are unknown. Tendon electrical stimulation to the Achilles' tendon was used to probe changes in Ib inhibition in medial gastrocnemius with postural orientation (lying prone vs. upright standing; experiment 1) and height-induced postural threat (standing at low and high surface heights; experiment 2). Ib inhibition was reduced while participants stood upright, compared to lying prone (42.2%); and further reduced when standing in the high, compared to low, threat condition (32.4%). These experiments will impact future research because they demonstrate that tendon electrical stimulation can be used to probe Ib reflexes in muscles engaged in standing balance. These results provide novel evidence that human short-latency GTO-Ib reflexes are dependent upon both task, as evidenced by changes with postural orientation, and context, such as height-induced postural threat during standing. Golgi tendon organ Ib reflexes are thought to contribute to standing balance control, but it is unknown if they are modulated when people are exposed to a postural threat. We used a novel application of tendon electrical stimulation (TStim) to elicit Ib inhibitory reflexes in the medial gastrocnemius, while actively engaged in upright standing balance, to examine (a) how Ib reflexes to TStim are influenced by upright stance, and (b) the effects of height-induced postural threat on Ib reflexes during standing. TStim evoked short-latency (<47 ms) inhibition apparent in trigger-averaged rectified EMG, which was quantified in terms of area, duration and mean amplitude of inhibition. In order to validate the use of TStim in a standing model, TStim-Ib inhibition was compared from conditions where participants were lying prone vs. standing upright. TStim evoked Ib inhibition in both conditions; however, significant reductions in Ib inhibition area (42.2%) and duration (32.9%) were observed during stance. Postural threat, manipulated by having participants stand at LOW (0.8 m high, 0.6 m from edge) and HIGH (3.2 m, at edge) elevated surfaces, significantly reduced Ib inhibition area (32.4%), duration (16.4%) and amplitude (24.8%) in the HIGH, compared to LOW, threat condition. These results demonstrate TStim is a viable technique for investigating Ib reflexes in standing, and confirm Ib reflexes are modulated with postural orientation. The novel observation of reduced Ib inhibition with elevated postural threat reveals that human Ib reflexes are context dependent, and the human Ib reflex pathways are modulated by threat or emotional processing centres of the CNS.


Prognostic value of blood pressure in acute stroke.
Manipulation of blood pressure (BP) in acute stroke may improve outcome. Despite various studies, data on the prognostic significance of early BP in stroke remain unclear. Therefore, we studied the relationship between various BP variables in the acute phase of stroke and functional outcome at 3 months. Blood pressures were collected by reviewing BP records of 817 patients who were admitted to our stroke unit between 1987 and 1992. Besides the first systolic and diastolic admission BP (SBP and DBP), we also used the mean of the daytime as well as the night-time systolic and diastolic BP values. Finally, we studied the relationship between the decrease in BP between day 0 and 4 and outcome. As dependent outcome variable we used the Rankin handicap score at 3 months dichotomized in a score >3 (poor outcome) vs a score 3 (good outcome). A total of 430 patients were admitted within 24 h following stroke onset. There was no significant relationship between the systolic and diastolic BP and the outcome at 3 months. Only night-time systolic BP 165 mm Hg (odds ratio (OR) 2.8; 95% CI 1.1-6.8), night-time diastolic BP 60 mm Hg (OR 8.1; 95% CI 1.1-58.3), and a decrease in daytime diastolic BP between day 0 and 4 of 10 mm Hg (OR 3.0; 95% CI 1.1-7.9) showed a significant relationship with poor outcome. Our findings suggest that admission BP values may not reliably reflect any impact of BP on stroke outcome. They also suggest a potential differential effect of BP manipulation: increasing or decreasing BP may be beneficial for patients with BP extremes in one direction, but detrimental for those with BP values in the opposite direction.


The synergistic effects of NGF and IGF-1 on neurite growth in adult sensory neurons: convergence on the PI 3-kinase signaling pathway.
Nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin-independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF-1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3-K-Akt-GSK-3 and Ras-Raf-MAPK) were performed using phospho-specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3-K pathway involving both Akt and GSK-3 appeared to be more important for neurite extension and branching than MAPK-dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho-Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3-K-Akt-GSK-3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth.


Sequential oxidation of 5-hydroxymethylfurfural to furan-2,5-dicarboxylic acid by an evolved aryl-alcohol oxidase.
Furan-2,5-dicarboxylic acid (FDCA) is a building block of biodegradable plastics that can be used to replace those derived from fossil carbon sources. In recent years, much interest has focused on the synthesis of FDCA from the bio-based 5-hydroxymethylfurfural (HMF) through a cascade of enzyme reactions. Aryl-alcohol oxidase (AAO) and 5-hydroxymethylfurfural oxidase (HMFO) are glucose-methanol-choline flavoenzymes that may be used to produce FDCA from HMF through three sequential oxidations, and without the assistance of auxiliary enzymes. Such a challenging process is dependent on the degree of hydration of the original aldehyde groups and of those formed, the rate-limiting step lying in the final oxidation of the intermediate 5-formyl-furancarboxylic acid (FFCA) to FDCA. While HMFO accepts FFCA as a final substrate in the HMF reaction pathway, AAO is virtually incapable of oxidizing it. Here, we have engineered AAO to perform the stepwise oxidation of HMF to FDCA through its structural alignment with HMFO and directed evolution. With a 3-fold enhanced catalytic efficiency for HMF and a 6-fold improvement in overall conversion, this evolved AAO is a promising point of departure for further engineering aimed at generating an efficient biocatalyst to synthesize FDCA from HMF.


Mental health status and use of general medical services for persons with human immunodeficiency virus.
Serious medical illness often is accompanied by psychological distress. Individuals experiencing mental disorders or symptoms have higher rates of morbidity and mortality, worse social functioning, and use of general medical services. We sought to examine the association between mental health and use of general medical services for persons in care for HIV. We used longitudinal data from the HIV Cost and Services Utilization Study (HCSUS), a nationally representative sample of 2267 HIV+ adults receiving care and who completed all 3 interviews during an 18-month period. Probability of use and general medical expenditures, by type of service. HIV+ individuals who screened positive for depression or had 5 or more mental health symptoms at baseline spent 20% to 25% more for general medical services in the following 12 months than HIV+ adults without mental health symptoms, after adjusting for disease severity and patient characteristics. Higher spending was largely the result of greater use of inpatient and emergency services. Psychological distress remains an independent predictor of general medical service use, although the magnitude of effect diminishes with better controls for physical well-being and previous service use. Identifying HIV patients with symptoms of affective or anxiety disorders may reduce overall treatment costs modestly.


Binding of catecholamines to alpha-1 acid glycoprotein, albumin and lipoproteins in human serum.
The binding of catecholamines in human serum was determined by equilibrium dialysis at 37 degrees. For serum concentrations of 10-15 nM the bound fractions were 28.8 +/- 2.2%, 25.7 +/- 1.7% and 22.2 +/- 2.2% for (+/-)-isoproterenol (IPR), (+/-)-norepinephrine (NE) and (+/-)-epinephrine (EPI), respectively. At higher serum concentrations saturation occurred. Alpha-1 acid glycoprotein (AAG) possessed one high affinity binding site and approximately 10 low affinity sites. The catecholamines were bound to AAG with the same order of potency for both classes of binding sites: IPR (Kd1: 100 microM Kd2: 2.2 mM) greater than NE (Kd1: 120 microM, Kd2: 6.5 mM) greater than EPI (Kd1: 140 microM, Kd2: 14 mM). Human serum albumin (HSA) and lipoproteins (SLP) interacted with the catecholamines in a non-saturable manner. IPR showed the strongest and EPI the weakest association to both of these serum protein fractions. (-)-Propranolol was able to inhibit the binding of IPR in serum and to isolated AAG, but not to HSA or to SLP. The present results show that AAG is an important catecholamine-binding protein in human serum. AAG, but not HSA or SLP, possesses binding sites shared by adrenergic receptor stimulators and blockers.


Inhibition of JNK in synovium by treatment with golimumab in rheumatoid arthritis.
The aim of this study was to investigate immunohistological changes in mitogen-activated protein kinases (MAPKs) in the synovium following treatment with golimumab, compared with methotrexate (MTX). We assessed synovial tissues for 13 different molecules to detect cytokine levels histologically from 10 methotrexate (MTX)-treated rheumatoid arthritis (RA) patients as controls and 10 golimumab plus MTX-treated RA patients. Synovium samples from both groups were assessed by hematoxylin and eosin (HE) staining and analyzed for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cells), CD8 (T cells), CD20 (B cells), CD68 (macrophages), receptor activator of nuclear (kappa) B ligand (RANKL), bromodeoxyuridine (BrdU), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (ERK1/ERK2), and phospho-c-Jun N-terminal kinase (JNK), by an immunohistological examination. HE staining showed that there was a significant decrease in cell proliferation in the synovium in RA patients who received golimumab compared with the controls. TNF-α, IL-6, MMP3, BrdU, p38, and ERK were not seen at significant levels in either group. On the other hand, CD4, CD8, CD20, CD29, CD68, RANKL, and JNK were significantly decreased in the golimumab group compared with the control. Based on a histological analysis of the synovium, it appears that the efficacy of the treatment with golimumab may involve the inhibition of cell proliferation, with decreases in T cells, B cells, macrophages, β-1 integrin, RANKL, and JNK in the synovium, compared with MTX treatment, in RA.


A unique C-terminal domain contributes to the molecular function of Restorer-of-fertility proteins in plant mitochondria.
Restorer-of-fertility (Rf) genes encode pentatricopeptide repeat (PPR) proteins that are targeted to mitochondria where they specifically bind to transcripts that induce cytoplasmic male sterility and repress their expression. In searching for a molecular signature unique to this class of proteins, we found that a majority of known Rf proteins have a distinct domain, which we called RfCTD (Restorer-of-fertility C-terminal domain), and its presence correlates with the ability to induce cleavage of the mitochondrial RNA target. A screen of 219 angiosperm genomes from 123 genera using a sequence profile that can quickly and accurately identify RfCTD sequences revealed considerable variation in RFL/RfCTD gene numbers across flowering plants. We observed that plant genera with bisexual flowers have significantly higher numbers of RFL genes compared to those with unisexual flowers, consistent with a role of these proteins in restoration of male fertility. We show that removing the RfCTD from the RFL protein RNA PROCESSING FACTOR 2-nad6 prevented cleavage of its RNA target, the nad6 transcript, in Arabidopsis thaliana mitochondria. We provide a simple way of identifying putative Rf candidates in genome sequences, new insights into the molecular mode of action of Rf proteins and the evolution of fertility restoration in flowering plants.


Development and validation of a nomogram for evaluating the prognosis of immunotherapy plus antiangiogenic therapy in non-small cell lung cancer.
With the combination therapy of PD-1/PD-L1 antibody and antiangiogenic drugs used widely in clinic, a novel method to estimate the prognosis of patients is needed. We aimed to develop a nomogram to examine prognosis of anti-PD-1/PD-L1 antibody plus bevacizumab in non-small cell lung cancer (NSCLC) patients. We developed a nomogram using the cohort involving 204 NSCLC patients who treated with immunotherapy and anti-angiogenesis therapy. The nomogram was validated under the same conditions in another cohort with 69 patients. Prognostic factors were analyzed by Cox regression analysis. The nomogram was internally validated using bootstrap resampling and then externally validated. Performance was assessed using concordance index, calibration curve and decision curve analysis. Clinical utility was evaluated using receiver operation characteristic curve. Pleural metastasis (P = 0.001, HR = 2.980, 95%CI 1.521-5.837), ANC (P < 0.001, HR = 5.139, 95%CI 2.081-12.691), ALC (P = 0.010, HR = 0.331, 95%CI 0.142-0.771), B cells (P = 0.005, HR = 0.329, 95%CI 0.151-0.714), Treg cells (P = 0.002, HR = 2.934, 95%CI 1.478-5.826) were independent prognostic factors. The calibration curves showed good consistency and the C-index of nomogram were 0.808, 0.741 in training and external validation cohort, respectively. The area under the curve (AUC) in receiver operation characteristic curves (ROC) are 0.833 (P < 0.001) and 0.908 (P < 0.001), respectively. We build an accurate and convenient nomogram to predict long-time overall survival (OS) of NSCLC patients treated with PD-1/PD-L1 antibody and antiangiogenic drugs and validated this nomogram. The nomogram might be helpful to clinicians to estimate long-time OS of NSCLC patients treated with PD-1/PD-L1 antibody and antiangiogenic drugs.


Horizontal Transmission of Metarhizium anisopliae in Fruit Flies and Effect of Fungal Infection on Egg Laying and Fertility.
Fly-to-fly transmission of conidia of the entomopathogenic fungus Metarhizium anisopliae and the effect of fungal infection on the reproductive potential of females surviving infection were investigated in three fruit fly species, Ceratitis cosyra, C. fasciventris, and C. capitata. The number of conidia picked up by a single fruit fly was determined in C. cosyra. The initial uptake (Day 0) of conidia by a single fly was approx. 1.1 × 10⁶ conidia after exposure to the treated substrate. However, the number of conidia dropped from 7.2 × 10⁵ to 4.1 × 10⁵ conidia after 2 and 8 h post-exposure, respectively. The number of conidia picked up by a single fungus-treated fly ("donor") varied between 3.8 × 10⁵ and 1.0 × 10⁶ in the three fruit fly species, resulting in 100% mortality 5-6 days post-exposure. When fungus-free flies of both sexes ("recipient" flies) were allowed to mate with "donor" flies, the number of conidia picked up by a single fly varied between 1.0 × 10⁵ and 2.5 × 10⁵, resulting in a mortality of 83-100% in C. capitata, 72-85% in C. cosyra and 71-93% in C. fasciventris 10-15 days post-inoculation. There was an effect of fungal infection on female egg laying in the three species of fruit flies as control flies laid more eggs than fungus-treated females. The percentage reduction in fecundity in flies infected with M. anisopliae was 82, 73 and 37% in C. capitata, C. fasciventris and C. cosyra, respectively. The results are discussed with regard to application in autodissemination techniques.


Lipoxin A4 interferes with embryo implantation via suppression of epithelial-mesenchymal transition.
To test whether lipoxin A4 (LXA4) interferes with embryo implantation via suppression of epithelial-mesenchymal transition (EMT). We developed a mouse model of LXA4 blocking embryo implantation and detected the indicators of EMT to confirm that LXA4 inhibits EMT might be a mechanism of interfering with the embryo implantation. We detected integrin-linked kinase (ILK), N-formylpeptide receptor 2 (FPR2), vascular endothelial growth factor, matrix metalloproteinases (MMPs), Akt, GSK3β, NF-ĸB, twist, vimentin, fibronectin, and β-catenin mRNA expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR; localized protein expression using immunohistochemistry and Western blotting assay; MMPs activity assay by gelatin zymography; and the status of implantation in pregnant animals assessed by pontamine blue reaction test. Preimplantation administration of LXA4 resulted in implantation failure. LXA4 has a time- and dose-dependent effect on embryo implantation. Day 0.5 after fertilization is the most effective time to use LXA4 to block embryo implantation. (a) LXA4 reduced endometrial stroma edema; (b) LXA4 inhibited the activity of MMP9 and significantly upregulated the expression of β-catenin, and downregulated the expression of vimentin, fibronectin, twist, NF-κB, Akt, and Gsk-3β in the endometrium and TEV-1 cells; (c) LXA4 upregulated the expression of FPR2, and downregulated the expression of ILK; FPR2-overexpressing had an inhibitory effect on ILK in TEV-1 cells. LXA4 inhibits EMT which attenuates ILK action by enhancing FPR2; therefore, this might be a mechanism of interfering with embryo implantation.


Measurement of adenoma detection and discrimination during colonoscopy in routine practice: an exploratory study.
Measuring neoplasia yield is a priority in the quality improvement process for colonoscopy. However, neither the most appropriate quality indicator nor the standard threshold has been established. To determine the most appropriate quality indicators to assess the yield of routine colonoscopy. Retrospective. Population-based colorectal cancer screening program in 3 French administrative areas. One hundred gastroenterologists and their average-risk asymptomatic patients aged 50 to 74 years undergoing colonoscopy for positive guaiac-based fecal occult blood test results. Comparison of several indicators, mainly the adenoma detection rate (ADR) and polyp detection rate (PDR), the mean number of adenomas per colonoscopy (MNA) and mean number of polyps (MNP) and the proportion of adenomas among polyps (PAP). Correlations were good between the ADR and PDR (Pearson coefficient r = 0.88 [95% CI, 0.78-0.94]) and between MNA and MNP (r = 0.89 [95% CI, 0.79-0.94]) (P < .0001 for both). Gastroenterologists were classified as higher or lower detectors in comparison with the lower limit of the 95% confidence interval of the median value for each indicator. The MNP (MNA) provided better discrimination than the PDR (ADR). Concordance between classifications of gastroenterologists according to their MNA and MNP was excellent (κ = 0.89). PAP varied dramatically from 38% to 95% between gastroenterologists and was very poorly correlated with the ADR (r = -0.27 [95% CI, -0.54 to 0.07; P = .11]) and the MNA (r = 0.03 [95% CI, -0.29 to 0.36; P = .88]). Some factors influencing the neoplasia yield were not taken into account. The MNP could replace the ADR for the assessment of adenoma detection in routine practice. A separate indicator, PAP, would be necessary to assess adenoma discrimination ability.


Synthesis and antifungal activity of C-21 steroids with an aromatic D ring.
Six analogues of salpichrolides with a simplified side chain (6-11) were synthesized using a new methodology to obtain steroids with an aromatic D-ring. The key step was the elimination of HBr in a vicinal dibromo D-homosteroid by treatment with 1,4-diazabicyclo[2.2.2]octane (DABCO). All new compounds were completely characterized by 2D NMR techniques and tested on two fungal pathogenic species, Fusarium virguliforme and Fusarium solani.