Tandem Amplification of the Staphylococcal Cassette Chromosome mec Element Can Drive High-Level Methicillin Resistance in Methicillin-Resistant Staphylococcus aureus.
Hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains typically express high-level, homogeneous (HoR) β-lactam resistance, whereas community-associated MRSA (CA-MRSA) more commonly express low-level heterogeneous (HeR) resistance. Expression of the HoR phenotype typically requires both increased expression of the mecA gene, carried on the staphylococcal cassette chromosome mec element (SCCmec), and additional mutational event(s) elsewhere on the chromosome. Here the oxacillin concentration in a chemostat culture of the CA-MRSA strain USA300 was increased from 8 μg/ml to 130 μg/ml over 13 days to isolate highly oxacillin-resistant derivatives. A stable, small-colony variant, designated HoR34, which had become established in the chemostat culture was found to have acquired mutations in gdpP, clpX, guaA, and camS Closer inspection of the genome sequence data further revealed that reads covering SCCmec were ∼10 times overrepresented compared to other parts of the chromosome. Quantitative PCR (qPCR) confirmed >10-fold-higher levels of mecA DNA on the HoR34 chromosome, and MinION genome sequencing verified the presence of 10 tandem repeats of the SCCmec element. qPCR further demonstrated that subculture of HoR34 in various concentrations of oxacillin (0 to 100 μg/ml) was accompanied by accordion-like contraction and amplification of the SCCmec element. Although slower growing than strain USA300, HoR34 outcompeted the parent strain in the presence of subinhibitory oxacillin. These data identify tandem amplification of the SCCmec element as a new mechanism of high-level methicillin resistance in MRSA, which may provide a competitive advantage for MRSA under antibiotic selection.


Cytochrome P-450-related arachidonic acid metabolites.
Arachidonic acid (AA) can be metabolized to diverse products that differ widely in their biologic activities. Depending on the cell type, AA can be metabolized by 3 pathways: cyclooxygenase, lipoxygenases, and cytochrome P-450 monooxygenases. Disease states, injury, and stress, will influence the enzymes that regulate the breakdown of AA and may favor the generation of products not usually associated with a tissue. Studies on renal eicosanoid mechanisms (all AA metabolites) can serve as a paradigm for other tissues and organs. Discrete stimulation of renal AA metabolism can occur-localized to specific cells within segments of the nephron; for example, cells of the medullary segment of the thick ascending limb of the loop of Henle (mTALH) have high cytochrome P-450 monooxygenase activity, through which novel AA metabolites are formed. These metabolites have characteristic biologic activities, inhibition of Na+-K+-ATPase activity and relaxation of blood vessels, and can be stimulated by peptide hormones. Cytochrome P-450-dependent monooxygenases are also present in the lung where, in their suggested capacity as oxygen sensors, they generate metabolites of AA that modify pulmonary vasomotion.


Anthraquinone: a promising scaffold for the discovery and development of therapeutic agents in cancer therapy.
Cancer, characterized by uncontrolled malignant neoplasm, is a leading cause of death in both advanced and emerging countries. Although, ample drugs are accessible in the market to intervene with tumor progression, none are totally effective and safe. Natural anthraquinone (AQ) equivalents such as emodin, aloe-emodin, alchemix and many synthetic analogs extend their antitumor activity on different targets including telomerase, topoisomerases, kinases, matrix metalloproteinases, DNA and different phases of cell lines. Nano drug delivery strategies are advanced tools which deliver drugs into tumor cells with minimum drug leakage to normal cells. This review delineates the way AQ derivatives are binding on these targets by abolishing tumor cells to produce anticancer activity and purview of nanoformulations related to AQ analogs.


Patient education. A review of the issues.
Patient education has become an increasingly important area of research during the last 30 years. This review examines the variety of issues within this field during the last decade. It concludes that preoperative education has proven beneficial in the subjective and objective improvement of patient recovery, particularly when procedural information and coping skills are provided. Further research is needed to determine the effects of sensory information, the timing of information provision and patient personality. Patient education programs should be interactive; this is particularly true for children, where such programs need to be age-specific. Lack of coordination of education services (due in part to the territoriality of patient educators), in addition to inadequate training of physicians and nurses, and absence of commitment by administration, are all significant barriers to effective patient education today. Finally, further reflection on the motivation behind patient education is needed. Many would argue that patient education has been used to serve the needs of the health care professional (through compliance) rather than empowering the patient. Implications for future research and recommendations for implementation are offered.


Embryonic Stem Cell-Derived Neurons Grown on Multi-Electrode Arrays as a Novel In vitro Bioassay for the Detection of Clostridium botulinum Neurotoxins.
Clostridium botulinum neurotoxins (BoNTs) are the most poisonous naturally occurring protein toxins known to mankind and are the causative agents of the severe and potentially life-threatening disease botulism. They are also known for their application as cosmetics and as unique bio-pharmaceuticals to treat an increasing number of neurological and non-neurological disorders. Currently, the potency of biologically active BoNT for therapeutic use is mainly monitored by the murine LD50-assay, an ethically disputable test causing suffering and death of a considerable number of mice. The aim of this study was to establish an in vitro assay as an alternative to the widely used in vivo mouse bioassay. We report a novel BoNT detection assay using mouse embryonic stem cell-derived neurons (mESN) cultured on multi-electrode arrays (MEAs). After 21 days in culture, the mESN formed a neuronal network showing spontaneous bursting activity based on functional synapses and express the necessary target proteins for BoNTs. Treating cultures for 6 h with 16.6 pM of BoNT serotype A and incubation with 1.66 pM BoNT/A or 33 Units/ml of Botox® for 24 h lead to a significant reduction of both spontaneous network bursts and average spike rate. This data suggests that mESN cultured on MEAs pose a novel, biologically relevant model that can be used to detect and quantify functional BoNT effects, thus accelerating BoNT research while decreasing animal use.


Fate of Ascaris at various pH, temperature and moisture levels.
Soil-transmitted helminths (STH) are intestinal worms that infect 24% of the world's population. Stopping the spread of STH is difficult, as the eggs are resilient (can withstand high pH) and persistent (can remain viable in soils for several years). To ensure that new sanitation systems can inactivate STH, a better understanding of their resilience is required. This study assessed the inactivation of Ascaris eggs under various conditions, in terms of moisture content (MC) (<20 to >90%), temperature (20-50 °C) and pH (7-12.5). The results highlight that the exposure of Ascaris eggs to elevated pH (10.5-12.5) at temperatures ≤27.5 °C for >70 days had no effect on egg viability. Compounding effects of alkaline pH (≥10.5) or decreasing MC (<20%) was observed at 35 °C, with pH having more of an effect than decreasing MC. To accelerate the inactivation of STH, an increase in the treatment temperature is more effective than pH increase. Alkaline pH alone did not inactivate the eggs but can enhance the effect of ammonia, which is likely to be present in organic wastes.


Gender differences in adult atopic dermatitis and clinical implication: Results from a nationwide multicentre study.
Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults. However, limited research has been conducted on gender differences in AD. This study aimed to assess gender differences in adult AD patients, focusing on demographic and clinical features, comorbidities and treatment approaches. In this multicentre, observational, cross-sectional study, we enrolled 686 adult patients with AD (357 males and 329 females). For each patient, we collected demographic data (age and sex), anthropometric measurements (weight, height, hip circumference, waist circumference and waist-to-hip ratio), clinical information (onset age, disease duration, severity, itching intensity, impact on quality of life) and noted comorbidities (metabolic, atopic and other). We recorded past and current topical and systemic treatments. We analysed all collected data using statistical techniques appropriate for both quantitative and qualitative variables. Multiple correspondence analysis (MCA) was employed to evaluate the relationships among all clinical characteristics of the patients. We found no differences in age at onset, disease duration, severity and quality of life impact between males and females. Males exhibited higher rates of hypertriglyceridaemia and hypertension. No significant gender differences were observed in atopic or other comorbidities. Treatment approaches were overlapping, except for greater methotrexate use in males. MCA revealed distinct patterns based on gender, disease severity, age of onset, treatment and quality of life. Adult males with AD had severe disease, extensive treatments and poorer quality of life, while adult females had milder disease, fewer treatments and moderate quality of life impact. Our study reveals that gender differences in adult AD patients are largely due to inherent population variations rather than disease-related disparities. However, it highlights potential undertreatment of females with moderate AD and quality of life impact, emphasizing the need for equitable AD treatment. JAK inhibitors may offer a solution for gender-based therapeutic parity.


Robotic-assisted excision of a juxta renal retroperitoneal schwannoma.
Retroperitoneal schwannoma is a rare benign tumor of the peripheral nerve Schwann sheath. We, herein, report the case of a 74-year-old woman who presented with vague abdominal pain. Computed tomography imaging revealed a retroperitoneal mass that is medial to the right kidney. The patient underwent robotic excision of the tumor with the pathology revealing schwannoma. We report this case due to the scarcity of this disease entity, especially at this location and to emphasize the indication and value of robotic technology in different pathological processes retroperitoneally.


Challenges simulating the AMOC in climate models.
The latest assessment report from the Intergovernmental Panel on Climate Change concluded that the Atlantic Meridional Overturning Circulation (AMOC) was very likely to decline over the twenty-first century under all emissions scenarios; however, there was low confidence in the magnitude of the decline. Recent research has highlighted that model biases in the mean climate state can affect the AMOC in its mean state, variability and its response to climate change. Hence, understanding and reducing these model biases is critical for reducing uncertainty in the future changes of the AMOC and in its impacts on the wider climate. We discuss how model biases, in particular salinity biases, influence the AMOC and deep convection. We then focus on biases in the UK HadGEM3-GC3-1 climate model and how these biases change with resolution. We also discuss ongoing model development activities that affect these biases, and highlight priorities for improved representation of processes, such as the position of the North Atlantic Current, transports in narrow boundary current, resolution (or improved parameterization) of eddies and spurious numerical mixing in overflows. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.


Physicochemically modified high-resolution tin oxide thin film using soft imprinting.
We carried out nanoimprinting lithography on solution-processed tin oxide (SnO) film for use as a liquid crystal (LC) alignment layer, for which we used a parallel configuration. To transfer the nanostructures onto the SnO film, we conducted an experiment according to curing, from which fine nanostructures on the SnO film were obtained at a curing temperature of 200 °C. These acted as a guide for the arrangement of the LC molecules and induced geometric restriction which minimized elastic distortion energies, and so the LC molecules could be aligned in the direction of the nanostructures. The LC alignment state was investigated using polarized optical microscopy, and the pre-tilt angle was measured using a crystal rotation method. With high thermal endurance and drastically low power consumption, the nano patterned SnO was shown to be a promising candidate for LC applications. The nanopatterning process combined with nanoimprinting lithography and solution-processed inorganic materials exhibited the possibility of broadening the features of nanostructure-mounted applications, including LC devices.


Extended storage and glucose exhaustion are associated with apoptotic changes in platelets stored in additive solution.
The storage of platelets (PLTs) in additive solution (AS) may facilitate improved PLT quality and possibly extension of the PLT shelf life. A minimum amount of plasma is required when PLTs are stored in AS, as a source of glucose. The aim of this study was to assess the effect of reducing the plasma carryover to 20% on PLT quality when stored in SSP+ for an extended period. Using a pool-and-split design, buffy coat-derived PLTs were stored in either 30% plasma/SSP+ or 20% plasma/SSP+. In vitro analyses were carried out to Day 10. Metabolites and markers of PLT activation and apoptosis were measured using a blood gas analyzer and flow cytometry. PLT apoptotic protein expression was investigated by Western blotting. Glucose exhaustion occurred in the 20% plasma group between Day 7 and Day 10. The surface expression of P-selectin and PAC-1 was comparable on Day 10 in both groups, suggesting that the PLTs were not activated. However, the exposure of phosphatidylserine and the number of phosphatidylserine-positive microparticles were significantly higher in the 20% group on Day 10. The expression of the proapoptotic proteins Bak, Bax, and cleaved caspase-3 were higher in the 20% plasma group by Day 7 of storage, compared to the 30% plasma group. Exhaustion of glucose was associated with a proapoptotic phenotype. Results such as these should be considered before extending the PLT shelf life beyond 7 days, particularly when stored in ASs lacking glucose with low plasma carryover.


Outcomes of double level osteotomy for osteoarthritic knees with severe varus deformity. A systematic review.
When correcting severe genu varus deformity, knee surgeons must choose between performing a single or double-level osteotomy. This systematic review aims to provide this equipoise with some clarity. We conducted this study following the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement (PRISMA) and the Cochrane Handbook for systematic reviews and meta-analysis. Studies evaluating the effect of the double level osteotomy (DLO) or those comparing it to high tibial osteotomy (HTO) from all regions and written in any language were included. Six studies were included in this systematic review. They were prepared and analysed using Review Manager V5.0 [Computer Program] (RevMan5). Performing DLO resulted in restoring patellar height, joint-line convergence angle (JLCA), and mMPTA to normal values. DLO was also more successful at avoiding joint line obliquity (JLO) in severe varus deformity when compared to HTO (P < 0.001). No significant difference was reported between the two cohorts regarding the mLPTA. DLO resulted in satisfactory short term KOOS and IKDC scores. The complication rate after DLO was 2.28%. DLO showed a low complication rate and satisfactory short term KOOS and IKDAC scores. Randomised control trials with long term follow-up comparing the DLO and HTO are recommended.


An Experimental Study on Defect Detection of Anchor Bolts Using Non-Destructive Testing Techniques.
Anchor bolts are often used for fixing information boards, supports, and soundproof walls in various facilities. Corrosion of anchor bolts and fatigue cracks occur frequently due to the various external environments, and visual inspection and hammering inspection are mainly used. In visual inspection, it is difficult to confirm corrosion or fatigue cracks of anchor bolts in the area where foundations, nuts, and base plates are installed. Additionally, the hammering inspection is easily affected by the surrounding environment and the subjective reaction of the tester. Therefore, it is necessary to develop a method that can easily and accurately detect defects such as cracks and corrosion occurring in anchor bolts installed in road facilities using non-destructive testing techniques. In this paper, the possibility and reliability of anchor bolt defects such as corrosion and cracks were experimentally verified by applying ultrasonic inspection among non-destructive inspection techniques for anchor bolt maintenance.


Growth curves: a method of monitoring established long-term primary human tumor cell cultures for autologous immunotherapy.
Cytomorphologic methods evidentiate tumor cells (TC) and differentiate them from fibroblasts, but are not indicated f for long term cultures. Growth rate and curve shape of TC and autologous fibroblasts cultures were recorded and compared over 4 weeks. Both were morphologically documented ex vivo and after MGG stain. No fibroblast overgrowth was noted in the TC cultures. The cultures showed rather peculiar curves with little variability among TC cultures. The 1st-week rate was higher in the TC cultures (p < .01). Growth curve evaluation with ex vivo observation of the morphology is- an alternative method in monitoring TC cultures for autologous immunotherapy.


Ammonotely in a passerine nectarivore: the influence of renal and post-renal modification on nitrogenous waste product excretion.
Most aquatic vertebrates are ammonotelic, whereas terrestrial vertebrates are typically uricotelic or ureotelic. However, the principal form of nitrogenous waste product in the urine of an animal may vary, depending on environmental conditions. Anna's hummingbird (Calypte anna) was found to switch from uricotely at high ambient temperature (T(a)) to ammonotely at lower T(a), when energy demands and consequent nectar intake rates were high. In extension of this, we hypothesised that nectarivorous birds would switch from uricotely to ammonotely when water intake rates were high or when protein or salt intake rates were low. We examined the influence of water, electrolyte and protein intake and of T(a) on the excretion of ammonia, urea and urate (uric acid and its salts) in nectarivorous Palestine sunbirds (Nectarinia osea). The proportion of ammonia in ureteral urine and excreted fluid was not influenced by total water or salt intake or by T(a). Protein intake did not influence nitrogenous waste product concentrations in ureteral urine. However, when protein intake was reduced, the proportion of ammonia in excreted fluid was higher because of the reduced urate concentration. This reduction in urate concentration leads to 'apparent' ammonotely. We suggest that ammonotely may not be a unique feature of nectarivorous birds. It could occur in any species in which breakdown of urate in the hindgut allows the uric acid-nitrogen concentration in the excreta to fall below that of the ammonia-nitrogen concentration.


Actin Gamma 1, a new skin cancer pathogenic gene, identified by the biological feature-based classification.
Skin cancer is the most common form of cancer that accounting for at least 40% of cancer cases around the world. This study aimed to identify skin cancer-related biological features and predict skin cancer candidate genes by employing machine learning based on biological features of known skin cancer genes. The known skin cancer-related genes were fetched from database and encoded by the enrichment scores of gene ontology and pathways. The optimal features of the skin cancer related genes were selected with a series of feature selection methods, such as mRMR, IFS, and Random Forest algorithm. Quantitative PCR (Q-PCR) was performed for the predicted genes. Effects on proliferation and metastasis of skin cancer cell line A431 were detected through MTT and transwell assay. The effects on myosin light chain (MLC) phosphorylation of Actin Gamma 1 (ACTG1) were detected by Western blot. A total of 1233 GO terms and 55 KEGG pathway terms were identified as the optimal features for the depiction of skin cancer. According to those terms, 1134 possible skin cancer-related genes were predicted. We further identified 16 new biomarkers in expression and the classification model can predict skin cancer cases with 100% accuracy. Among the 16 genes, ACTG1 had significantly high expression in skin cancer tissue. Our investigation suggested that ACTG1 can regulate the cell proliferation and migration through ROCK signaling pathway.


[Estimated levels of fructosamine in venous blood of pregnant women and in cord blood].
In the study there was estimated maternal (Fm) and cord blood (Fc) fructosamine levels in 151 diabetic (58 PGDM and 93 GDM) and 100 control subjects on the day of delivery. It was found that Fm and Fc levels in PGDM and GDM groups were significantly higher than in the control group. It was also found the significantly positive correlation between Fm and Fc levels in all study groups. It leads to the conclusion that pregnant diabetic women and their fetuses were hyperglycemic during the last 2 weeks of pregnancy. Our results indicate that on the basis of maternal fructosamine levels it is possible to apply on indirect estimation of metabolic status of the fetus.


Adenovirus vaccine immunotherapy targeting WT1-expressing tumors.
Tumor associated antigens (TAAs) offer specific targets for developing cancer immunotherapies. In particular, viral vectors encoding transgenic TAAs have been used in recent vaccination strategies. Wilm's Tumor gene (WT1) is a robust TAA which is overexpressed in many malignancies and has been recently used to develop a novel recombinant adenovirus (Ad-WT1) for antitumor immunotherapy. The lines of evidence over the past two decades leading to the development of Ad-WT1 immunotherapy are reviewed, including preclinical studies and clinical trials using WT1-based vaccines and TAA-expressing adenoviral vectors for antitumor therapy. The fundamental immunogenic properties of WT1-based vaccines are detailed, as well as the recent progress in using adenoviral vectors for eliciting a TAA-specific immune response. The reader will also gain an understanding of the evidence supporting Ad-WT1 antitumor therapy in vivo. Ad-WT1 elicits a potent CD4(+) and CD8(+) T cell immune response and can effectively inhibit tumor growth in vivo, thus making it an important potential cancer therapy worthy of future investigation.


Effects of hydrochloric acid washing on the microstructure and pyrolysis bio-oil components of sweet sorghum bagasse.
Acid washing is an alternative and promising approach for biomass to produce high-quality bio-oil. The hydrochloric acid washing pretreatment of sweet sorghum bagasse was performed in this study. The effects of acid washing on the ultrastructure of sweet sorghum bagasse were investigated using scanning electron microscope and Fourier transform infrared, and the effects on pyrolysis using thermogravimetric analyzer and a fast pyrolysis device. The results indicated acid treatment obviously changed the surface morphology of the cell walls of sweet sorghum bagasse, effectively removed most metals from sweet sorghum bagasse, and increased the volatiles and bio-oil yields. The results showed that bio-oil produced from pretreated sweet sorghum bagasse contained less components categories, lower contents of phenols, aldehydes, furans and alcohols, while much higher contents of d-allose and ketones than that from the original sample. Hydrochloric acid-washing pretreatment of sweet sorghum bagasse can increase the contents of some high-value chemicals in bio-oil.


Zero and second-derivative synchronous fluorescence spectroscopy for the quantification of two non-classical β-lactams in pharmaceutical vials: Application to stability studies.
The formation of metal chelates with various ligands may lead to the production of fluorescent chelates or enhance the fluorescence of the chelating agent. This paper describes two sensitive, selective and computer-solved methods, namely, zero order (SF) and second-derivative synchronous spectrofluorimetry (SDSFS) for nano-quantitation of two carbapenems; meropenem (MP) and ertapenem (EP). The methods are based on the chelation of MP with Tb3+ and EP with Zr4+ in buffered organic medium at pH 4.0 to produce fluorescent chelates. In the zero order method, the relative synchronous fluorescence intensity is measured at 327.0 nm at Δλ = 70.0 and 100.0 nm for MP and EP, respectively. The second method utilizes a second-derivative technique to enhance the method selectivity and emphasize a stability-indicating approach. The peak amplitudes (2 D) of the second-derivative synchronous spectra were estimated to be 333.06 and 330.06 nm for MP and EP, respectively. The proposed synchronous spectrofluorimetric methods were validated according to the International Conference on Harmonization (ICH) guidelines and applied successfully for the analysis of MP and EP in pure forms, pharmaceutical vials and in synthetic mixtures with different degradants of both drugs. Under optimum conditions, the mole-ratio method was applied and the co-ordination ratios of MP-Tb3+ and EP-Zr4+ chelates were found to be 1:1 and 1:3. The formation constants for the chelation complexes were evaluated using the Benesi-Hildebrand's equation; the free energy change (ΔG) was also calculated. The results indicated that EP-Zr4+ was more stable than the MP-Tb3+ chelate. Moreover, the developed methods were found to be selective and inexpensive for quantitative determination of both drugs in quality control laboratories at nano-levels.


Highly Sensitive Squaraine-Based Water-Soluble Far-Red/Near-Infrared Chromofluorogenic Thiophenol Probe.
A squaraine-based far-red/near-infrared fluorescent probe (SQ-DNBS) was exploited for thiophenol detection. SQ-DNBS is a colorimetric and "off-on" fluorometric dual-channel "naked-eye" chemosensor showing high selectivity, high sensitivity (detection limit: 9.9 nM), and rapid response to thiophenol in aqueous solution. SQ-DNBS also can be used in practical applications for the detection of thiophenol in water samples. Photophysical and spectral characterization results revealed that the probing mechanism of SQ-DNBS toward thiophenol lies in the thiolate-mediated cleavage reaction. Our discovery demonstrates the potential of the arylmethylene-squaraine skeleton as a promising fluorophore unit to construct high-performance far-red/near-infrared chemosensors.


Effect of Xuebijing injection on peripheral T-lymphocyte subpopulations in patients with severe trauma.
To investigate the effect and clinical significance of Xuebijing injection on peripheral T-lymphocyte subpopulations in patients with severe trauma. Thirty-three patients with severe trauma were randomly divided into a control group (n=16) and a treatment group (n=17). The patients of two groups were all treated conventionally, and the only difference was that Xuebijing injection was given to patients of the treatment group. The CD4+ and CD8+ subpopulations of T-lymphocyte in the peripheral blood were detected respectively on admission, 3rd and 5th days after trauma by double antibody labeling and flow cytometry. The CD4+ T-lymphocytes and CD4+/CD8+ ratio of peripheral blood in patients with severe trauma decreased markedly on the 3rd and 5th days after trauma. Furthermore, compared with control group, the peripheral CD4+ T-lymphocytes and CD4+/CD8+ ratio of treatment group renewed obviously on the 5th day after trauma, and showed statistical differences (P<0.05). In the treatment of patients with severe trauma, the early use of Xuebijing injection is effective in correcting disorder or suppression of T-lymphocyte subpopulations regulating network, and promoting a more balanced profile of immunologic function.


Physical Inactivity as a Pandemic: Daily Activities and Dietary Practices.
Numerous studies have linked a decline in physical activity (PA) around the world to an increase in chronic diseases. There were two key goals for this study. The first was to observe how daily activities affected physical health in terms of VO2max. The second aim was to investigate the effect of university students' dietary practices on levels of PA. A repeated cross-sectional study was conducted on 75 subjects (41 males and 34 females) with an average age of 27.3 [SD 5.8] years. The respondents' physical activity in the previous seven days was classified as vigorous activity, moderate activity, walking, and sitting using the International Physical Activity Questionnaire (IPAQ). Anthropometric measurements such as height, weight, and body mass index (BMI) were reported at the baseline, during Lent (week 7 of the vegan diet), and seven weeks later (week 14). To determine Maximum Oxygen Consumption-the VO2max, the Queen's College Step Test [QCST] was used. There was a major difference in mean VO2max between males and females, with males getting a higher VO2max. There was no connection between VO2max and changes in dietary adherence/transition. Based on physical activity study, there were no major variations between subjects (walking Metabolic Equivalent Task (MET) and moderate MET). However, a thorough Vigorous MET showed major gender gaps. The majority of the participants in the current study spent 35 (46.7%) of their time studying and 19 (28%) of their time attending class lectures, with some students using more time than others. Researches that may conduct in university and/or college students may provide early information to help the students understand their physical fitness. According to the findings of this limited prospective study, students spend the majority of their time engaging in sitting for various purposes. In turn, regardless of whether they followed a vegan or omnivorous diet, these study participants had low VO2 max.


Immune and viral correlates of "secondary viral control" after treatment interruption in chronically HIV-1 infected patients.
Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral load rebound to pre-treatment levels. Four patients, hereafter referred to as secondary controllers (SC), were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T cell function and HIV neutralizing antibodies were investigated. As expected all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in PBMC as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low to absent growth in two cases and a virus with normal fitness in the third case. T cell responses toward HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells, as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of treatment.


Serological evidence of Mycoplasma cynos infection in canine infectious respiratory disease.
A high proportion of dogs suffer from respiratory disease when they are placed in kennels for vacation or re-homing. The role of Mycoplasma cynos as an initiating agent in canine infectious respiratory disease was investigated by examining the serological response of dogs to this organism at the time of entry into a large re-homing kennel. Forty-two paired serum samples from dogs (21-day interval) were examined for antibody to M. cynos using Western blotting. The development of antibody in the serum was related to clinical disease recorded over the same period. Sixty seven per cent of the dogs showed a two-fold or greater rise in antibody to M. cynos during the first 3 weeks in the kennel. Reactivity with a 45kDa antigen was dominant. Of those showing a positive serological reaction, 80% had recorded clinical respiratory disease while 20% remained healthy. The findings of this study show that an antibody response to M. cynos is common in dogs entering the re-homing kennel and is positively related to the development of clinical respiratory disease.


The updated view concerning the possibility of growing old without senescence.
New findings paradoxically highlight the capability of old mitochondria, precursor cells, tissues, and organs for rejuvenation during vital activity at appropriate conditions and modes. But most studies of aging are conducted in living beings situated in rather artificial conditions. Such external conditions are less adequate to the evolutionarily adjusted genetic construction of an organism and lead to the appearance of senescence due to incomplete self-maintenance processes. These arguments as well as other findings suggest that imitation of appropriate external signals or peculiar modification of control systems of an organism can lead to the state of full nonsenescence.


Taking a Third-Person Perspective Requires Inhibitory Control: Evidence From a Developmental Negative Priming Study.
To determine whether the growing ability to take a third-person perspective (3PP) is explained in part by the growing ability to inhibit a first-person perspective (1PP), 10-year-old children (n = 49) and 22-year-old adults (n = 52) performed a negative priming adaptation of the own body transformation task. Both children and adults were less efficient in adopting a 1PP after they adopted a 3PP-with a smaller amplitude of the negative priming effect with older age-and adults' and children's performances in the own body transformation task were predicted in part by their Stroop interference scores. These results suggest that the growing efficiency to adopt a 3PP is rooted in part in the growing efficiency to inhibit the 1PP.


Page kidney with constrictive perinephritis.
We describe a case of Page kidney following an infectious urinoma complicated by a pyelolithotomy. The most characteristic finding was the fact that this case resulted from constrictive perinephritis, not from any usual etiology such as perirenal hematoma. Knowledge of the patient's medical history and split venous renin measurements were helpful in making a diagnosis. She had refractory hypertension during conservative medical therapy. Finally, a nephrectomy improved her hypertension. The value of venous renin sampling for reaching a diagnosis, and the medical and surgical therapeutic options are discussed. This report also reviews all previously described cases of Page kidney without hematomas.


Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders.
Peppermint oil has been used for centuries as a treatment for gastrointestinal ailments. It has been shown to have several effects on gastrointestinal physiology relevant to clinical care and management. To review the literature on peppermint oil regarding its metabolism, effects on gastrointestinal physiology, clinical use and efficacy, and safety. We performed a PubMed literature search using the following terms individually or in combination: peppermint, peppermint oil, pharmacokinetics, menthol, oesophagus, stomach, small intestine, gallbladder, colon, transit, dyspepsia, nausea, abdominal pain, and irritable bowel syndrome. Full manuscripts evaluating peppermint oil that were published through 15 July 2017 were reviewed. When evaluating therapeutic indications, only randomised clinical trials were included. References from selected manuscripts were used if relevant. It appears that peppermint oil may have several mechanisms of action including: smooth muscle relaxation (via calcium channel blockade or direct enteric nervous system effects); visceral sensitivity modulation (via transient receptor potential cation channels); anti-microbial effects; anti-inflammatory activity; modulation of psychosocial distress. Peppermint oil has been found to affect oesophageal, gastric, small bowel, gall-bladder, and colonic physiology. It has been used to facilitate completion of colonoscopy and endoscopic retrograde cholangiopancreatography. Placebo controlled studies support its use in irritable bowel syndrome, functional dyspepsia, childhood functional abdominal pain, and post-operative nausea. Few adverse effects have been reported in peppermint oil trials. Peppermint oil is a natural product which affects physiology throughout the gastrointestinal tract, has been used successfully for several clinical disorders, and appears to have a good safety profile.


Isolation and characterization of temperature-sensitive mutants of adenovirus type2.
Fourteen temperature-sensitive mutants of human adenovirus type2, which differed in their plaquing efficiencies at at the permissive and nonpermissive temperatures by 4 to 5 orders of magnitude, were isolated. These mutants, which could be assigned to seven complementation groups, were tested for their capacity to synthesize adenovirus DNA at the nonpermissive temperature. Three mutants in three different complementation groups proved deficient in viral DNA synthesis. The DNA-negative mutant H2ts206 complemented the DNA-negative mutants H5ts36 and H5ts125, whereas mutant H2ts201 complemented H5ts36 only. Among the DNA-negative mutants, H2ts206 synthesized the smallest amount of viral DNA at the nonpermissive temperature (39.5 C). Data obtained in temperature shift experiments indicated that a very early function was involved in temperature sensitivity. In keeping with this observation, early virus-specific mRNA was not detected in cells infected with H2ts206 and maintained at 39.5 C. Prolonged (52 h) incubation of cells infected with H2ts206 at the nonpermissive temperature led to the synthesis of a high-molecular-weight form of viral DNA.


Characterizing cognitive and visuomotor control in children with sensory processing dysfunction and autism spectrum disorders.
Children with autism spectrum disorders (ASD) and sensory processing dysfunction (SPD) are reported to show difficulties involving cognitive and visuomotor control. We sought to determine whether performance on computerized, behavioral measures of cognitive control aimed at assessing selective attention, as well as visuomotor abilities differentiated children with ASD (n = 14), SPD (n = 14) and typically developing controls (TDC; n = 28). Cognitive control differences were measured by assessing selective attention-based abilities both with and without distracting stimuli, and visuomotor differences were measured by characterizing visuomotor tracking and tracing skills. Performance in cognitive control and visuomotor domains were investigated globally as composite scores, and specifically within each task. Our results indicated that though the ASD group showed the most impaired selective attention performance, the SPD group had intermediate abilities-performing above the ASD group but below the TDC group. Furthermore, both the SPD and ASD groups demonstrated equally impaired visuomotor abilities relative to the TDC group. A correlational analysis between cognitive and visuomotor control suggest a relationship between these overlapping control networks. This study supports the importance of direct, phenotypic characterizations of control-based abilities in children with ASD and SPD to personalize characterization and treatment interventions for at-risk children. (PsycINFO Database Record


Expression and clinical significance of LXRα and SREBP-1c in placentas of preeclampsia.
To evaluate the expression and correlations of liver X receptor alpha (LXRa) and its target gene sterol regulatory element-binding protein-1c (SREBP-1c) in placentas of preeclampsia (PE) and their significance in PE. Pregnancies were divided into two groups, 60 cases (29 cases of mild and 31 cases of severe) of PE group and 56 cases of normal group. The level of mRNA and protein of LXRa and SREBP-1c were analyzed by reverse transcription-polymerase chain reaction (RTPCR) and immunohistochemistry (IHC) in the placentas. RT-PCR and IHC results showed that the mRNA and protein expression of both LXRa and SREBP-1c increased gradually with the extent of PE among normal pregnancy, mild PE and severe PE groups, and the differences were of statistically significance (P<0.01 or P<0.05). There were positive correlations between the expression of LXRa mRNA and SREBP-1c mRNA, also between LXRa mRNA and LXRa protein (r=0.521, P<0.01; r=0.422, P<0.01). The expression of SREBP-1c mRNA positively correlated with its protein level (r=0.598, P<0.01). There were positive correlations between the expression of LXRa protein and SREBP-1c protein (r=0.612, P<0.01). The expression of LXRa is elevated significantly in placentas of PE patients, and might contribute for promoting the transcription and translation of its target gene SREBP1-c, which is related to the occurrence and development of PE.


Galanin Receptors as Drug Target for Novel Antidepressants: Review.
Galanin (GAL) is a 29-amino-acid neuropeptide that serves multiple physiological functions throughout the central and peripheral nervous system. Its role involves in a range of physiological and pathological functions including control of food intake, neuro-protection, neuronal regeneration, energy expenditure, reproduction, water balance, mood, nociception and various neuroendocrine functions. The use of currently available antidepressant drugs raises concerns regarding efficacy and onset of action; therefore, the need for antidepressants with novel mechanisms is increasing. Presently, various studies revealed the link between GAL and depression. Attenuation of depressive symptoms is achieved through inhibition of GalR1 and GalR3 and activation of GalR2. However, lack of receptor selectivity of ligands has limited the complete elucidation of effects of different receptors in depression-like behavior. Studies have suggested that GAL enhances the action of selective serotonin reuptake inhibitors (SSRIs) and promotes availability of transcription proteins. This review addresses the role of GAL, GAL receptors (GALRs) ligands including selective peptides, and the mechanism of ligand receptor interaction in attenuating depressive symptoms.


Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance.
Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes.


Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review.
Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a "stocking and glove" distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.


Active ingredients from natural botanicals in the treatment of obesity.
Obesity is considered as a chronic disease that can induce a series of comorbidities and complications. Chinese medicine has long clinical experiences in the treatment of obesity. This review summarizes the natural products from traditional Chinese medicine (TCM) that are reported to have anti-obesity effects in the past two decades. Botanic TCM comprises 90% of total Chinese crude drugs, and generally contains various active ingredients, in which the effective anti-obesity ingredients identified can be divided into saponins, polysaccharides, alkaloids, polyphenols and others. Astragaloside IV, glycyrrhizin, macrostemonoside A, berberine, betaine, capsaicin, matrine, methyl piperate, piperine, rutaecarpine, asimilobine, epigallocatechingallate, magnolol, resveratrol, soybean-isoflavone, α-linolenic acid, emodin, geniposide, phillyrin, salidroside and ursolic acid are specified in this review, and their sources, models, efficacy are described. It is concluded that the mechanisms of these components for the treatment of obesity include: (i) suppression of appetite, increase of satiety, reduction of energy intake; (ii) reduction in the digestion and absorption of exogenous lipid; (iii) attenuation of the synthesis of endogenous lipid; (iv) promotion of the oxidation and expenditure of lipid and (v) improvement of lipid metabolism disorder. Authors believe that the effective compounds from TCM will provide an alternative and hopeful way for the treatment of obesity.


Changes of number of cells expressing proliferation and progenitor cell markers with age in rabbit intervertebral discs.
Basic knowledge about the normal regeneration process within the intervertebral disc (IVD) is important to the understanding of the underlying biology. The presence of progenitor and stem cells in IVD has been verified. However, changes of number of progenitor and stem cells with age are still unknown. In this study, changes of cell proliferation and progenitor cell markers with age in IVD cells from rabbits of two different ages were investigated using flow cytometry, immunohistochemistry, real-time polymerase chain reaction, and western blot analysis. Proliferating cell nuclear antigen (PCNA) was chosen as a marker for proliferation, and Notch1, Jagged1, C-KIT, CD166 were chosen as stem/progenitor cell markers. Cell cycle analysis showed that cell number in the G2/M phase of the young rabbits was significantly higher than that of mature rabbits. Immunohistochemical staining demonstrated the expression of PCNA, C-KIT, CD166, Notch1, and Jagged1 in both young and mature annulus fibrosus (AF). Protein expressions of these cell markers in the young rabbits were all significantly higher than those in the mature rabbits. The expression levels of PCNA, CD166, C-KIT, Jagged1 were significantly higher in the AF, and PCNA, C-KIT in the nucleus pulposus from young rabbits than those from the mature rabbits. These findings demonstrated that both proliferation and progenitor cells exist in rabbit IVDs and the number of cells expressing proliferation and progenitor cell markers decreases with age in the rabbit IVD cells. Methods that are designed to maintain the endogenous progenitor cells and stimulate their proliferation could be successful in preventing or inhibiting degenerative disc disease.


Reproducibility of whole-brain temperature mapping and metabolite quantification using proton magnetic resonance spectroscopy.
Assessing brain temperature can provide important information about disease processes (e.g., stroke, trauma) and therapeutic effects (e.g., cerebral hypothermia treatment). Whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) is increasingly used to quantify brain metabolites across the entire brain. However, its feasibility and reliability for estimating brain temperature needs further validation. Therefore, the present study evaluates the reproducibility of WB-MRSI for temperature mapping as well as metabolite quantification across the whole brain in healthy volunteers. Ten healthy adults were scanned on three occasions 1 week apart. Brain temperature, along with four commonly assessed brain metabolites-total N-acetyl-aspartate (tNAA), total creatine (tCr), total choline (tCho) and myo-inositol (mI)-were measured from WB-MRSI data. Reproducibility was evaluated using the coefficient of variation (CV). The measured mean (range) of the intra-subject CVs was 0.9% (0.6%-1.6%) for brain temperature mapping, and 4.7% (2.5%-15.7%), 6.4% (2.4%-18.9%) and 14.2% (4.4%-52.6%) for tNAA, tCho and mI, respectively, with reference to tCr. Consistently larger variability was found when using H2 O as the reference for metabolite quantifications: 7.8% (3.3%-17.8%), 7.8% (3.1%-18.0%), 9.8% (3.7%-31.0%) and 17.0% (5.9%-54.0%) for tNAA, tCr, tCho and mI, respectively. Further, the larger the brain region (indicated by a greater number of voxels within that region), the better the reproducibility for both temperature and metabolite estimates. Our results demonstrate good reproducibility of whole-brain temperature and metabolite measurements using the WB-MRSI technique.


Role of Akt and mammalian target of rapamycin signalling in insulin-like growth factor 1-mediated cell proliferation in porcine Sertoli cells.
The critical role of insulin-like growth factor (IGF) 1 in promoting Sertoli cell proliferation invivo and invitro has been established, but its downstream signalling mechanisms remain unknown. In addition to mitogenic effects, a role for IGF1 in mediating cholesterol biosynthesis within testes has been implied. The aims of this study were to investigate the roles of: (1) phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signalling in IGF1-mediated Sertoli cell proliferation; and (2) IGF1 in mediating cholesterol biosynthesis in Sertoli cells. Primary cultures of Sertoli cells were prepared from 1-week-old porcine testes. On Day 3 of culture, Sertoli cells were treated with 300ng mL-1 IGF1, alone or in combination with inhibitors of IGF1 receptor (2μM picropodophyllotoxin), Akt (1μM wortmannin) or mTOR (200nM rapamycin). Cells were cultured for 30min and phosphorylation levels of Akt, mTOR and p70 ribosomal protein S6 kinase (p70S6K) were determined by immunoblotting. Cell proliferation and quantitative polymerase chain reaction assays were conducted using cells cultured for 24h. IGF1 increased phosphorylation of Akt, mTOR and p70S6K and cell proliferation, and these effects were inhibited by inhibitors of IGF1R, Akt and mTOR. Furthermore, IGF1 upregulated the expression of cholesterol biosynthetic genes (3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS1) and cytochrome P450, family 5, subfamily A, polypeptide 1 (CYP5A1)), but not sterol regulatory element-binding transcription factor 1 (SREBF1). Increased phosphorylation of p70S6K, a major downstream target of mTOR, and upregulated expression of genes involved in cholesterol biosynthesis are indicative of the key role played by IGF1 in regulating the synthesis of cholesterol, the precursor for steroid hormones.


Voltage-gated potassium channel antibody-related encephalopathy: a case which may extend the documented phenotype of this condition.
A 51-year-old man presented with a focal epileptic, fluctuating encephalopathy. Antibodies to voltage-gated potassium channels (VGKC-Abs) were detected in his serum. Several features of this case were different from those previously reported in VGKC-Ab-associated encephalitis, illustrating that it may have a broader phenotype than previously documented. These features were: excess hepatic iron deposits without cirrhosis, reduced consciousness and fluctuating neurological signs. Previous history included personality change, depression, type 2 diabetes mellitus, pupil sparing third nerve palsy and epilepsy secondary to a head injury. He had never drunk alcohol and had recovered from a similar episode 4 years previously. Both episodes resolved after approximately 2 months. The cerebrospinal fluid had a raised protein content but no organisms. The patient was heterozygous for C282Y and negative for H63D mutations excluding classical idiopathic haemochromatosis. He recovered with supportive care to his premorbid level of health.


Aortic arch advancement for type A interrupted aortic arch with persistent fifth aortic arch type B.
Persistence of the fifth aortic arch is a very rare anomaly, but is clinically relevant when it is associated with coarctation. We report a case of a neonate with type A interrupted aortic arch and severe coarctation of a persistent fifth aortic arch, which was discovered after repair of a left congenital diaphragmatic hernia. The combination of anomalies was discovered intra-operatively following left thoracotomy, and was treated with aortic arch advancement. The postoperative course was uneventful.


Important observations made managing carotid body tumors during a 25-year experience.
Our objective was to assess the short- and long-term outcome for patients after carotid body tumor (CBT) resection and discuss the potential pitfalls of the treatment. An analysis was undertaken of all patients who underwent CBT resection at Royal Brisbane and Women's Hospital and Greenslopes Private Hospital between 1982 and 2007. Primary tumor characteristics, surgical technique, and outcomes were recorded and analyzed. A total of 49 consecutive CBT resections (2 recurrent tumors) were carried out in 39 patients (26 women [56%]) who were a mean age of 49 years (range, 17-75 years). A nontender neck mass was the presenting complaint in 85%, followed by screening in familial or contralateral tumors in 26%. Familial cases occurred in 11 patients (28%). There were no operative deaths. Complications occurred in 13 of the 49 operations (27%), predominantly temporary nerve palsies and were more likely to occur in tumors of large volume or in cases of removal of coexisting vagal tumors. Malignant disease was present in seven cases (15%). All patients have been followed-up postoperatively for a mean of 11 years (range, 2-26 years). Metachronous paragangliomas have been discovered in six patients, all with familial disease. Early resection of carotid body tumors should be undertaken while still small to minimize the risk of neural injury, which increases with tumor size. In cases of bilateral CBT, we recommend that the smaller tumor be resected first, before the staged resection of the larger contralateral tumor. In familial or bilateral tumor cases, other synchronous and metachronous paragangliomas should be excluded. Mandatory lifelong follow-up is essential.


Expression of the interferon regulatory factor 8/ICSBP-1 in human reactive lymphoid tissues and B-cell lymphomas: a novel germinal center marker.
To assess the role of interferon regulatory factor (IRF) 8 in B-cell development and lymphomagenesis, we studied its expression in reactive lymphoid tissues, its relationship to other B-cell transcription factors, and its expression in a series of 232 B-cell tumors and 30 cell lines representing a variety of B-cell developmental stages. We found that although IRF8 was detectable in most reactive B-cells, its expression levels differed with developmental stage. Germinal center B cells contained the highest levels of IRF8, with lower levels seen in mantle and marginal zone B cells and none in plasma cells. IRF8 was coexpressed with PAX-5, Pu.1, and B-cell lymphoma (BCL)-6, and similar to BCL-6, was absent from the small population of IRF4-positive germinal center B cells thought to be committed to postgerminal center developmental programs. Similarly, IRF8 was most strongly expressed in lymphomas of germinal center origin with lower levels present in mantle cell lymphomas, chronic lymphocytic leukemia, and marginal zone lymphomas, and no expression observed in plasmacytic/plasmablastic neoplasms. The reciprocal expression pattern with IRF4 in reactive tissues was generally maintained in lymphomas with some exceptions. These results suggest an important role for IRF8 during germinal center B-cell development and in related lymphomas, and provide a new diagnostic marker helpful in distinguishing B-cell non-Hodgkin lymphoma subtypes.


Adoptive immunotherapy for head and neck cancer with killer cells induced by stimulation with autologous or allogeneic tumour cells and recombinant interleukin-2.
Peripheral blood lymphocytes drawn by leukapheresis using Haemonetics V50 were mixed and cultured with autologous or allogeneic tumour cell line to activate killer cells by tumour antigenic stimulation, and further with recombinant interleukin-2 (rIL-2). Killer cells were intra-arterially infused, as a primary therapy, in 5 patients with maxillary and one with lingual cancer (squamous cell carcinoma). Effects on reduction of primary tumour size were significantly high without any severe side effects. The effects were interpreted mainly by direct day-by-day observation of the site, findings of CT and histology. Histological findings of the tissue obtained by surgical operation performed after adoptive immunotherapy were remarkable changes, such as infiltration of lymphoid cells around the cancer nets, degeneration of cancer cells, infiltration of scavenger macrophages (giant cells) and so on. The results suggested that adoptive immunotherapy by the killer cells can be a powerful treatment to bring the cancer under control, in with combination of other therapies.


Is there an optimal time to initiate adjuvant chemotherapy to predict benefit of survival in non-small cell lung cancer?
Adjuvant chemotherapy (AC) after curative resection is known to improve the survival of patients with non-small cell lung cancer (NSCLC); however, few studies have reported the correlation between the time to initiation of AC (TTAC) and survival in NSCLC patients. The clinical data of 925 NSCLC patients who received curative resection and post-operative AC at the Cancer Hospital of Chinese Academy of Medical Sciences between 2003 and 2013 were retrospectively analyzed. TTAC was measured from the date of surgery to the initiation of AC. Disease-free survival (DFS) was defined as the duration from surgery to the time of tumor recurrence or last follow-up evaluation. The optimal cut-off value of TTAC was determined by maximally selected log-rank statistics. The DFS curve was estimated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to identify risk factors independently associated with DFS. Propensity score matching (PSM) was performed for survival analysis using the match data. The optimal discriminating cut-off value of TTAC was set at d 35 after curative resection based on which the patients were assigned into two groups: group A (≤35 d) and group B (>35 d). There was no significant difference in the DFS between the two groups (P=0.246), indicating that the TTAC is not an independent prognostic factor for DFS. A further comparison continued to show no significant difference in the DFS among 258 PSM pairs (P=0.283). There was no significant correlation between the TTAC and DFS in NSCLC patients. Studies with larger samples are needed to further verify this conclusion.


Ethnic comparison of haloperidol and reduced haloperidol plasma levels: Taiwan Chinese versus American non-Chinese.
Steady-state haloperidol (HAL) and reduced HAL (RHAL) plasma levels were measured in Chinese and non-Chinese schizophrenic patients. The patients (n = 38) were matched according to age (+/- 1 yr) and by HAL dose. In general, Chinese patients had higher mean plasma HAL levels and lower RHAL/HAL ratios compared to non-Chinese patients (23.6 +/- 14.9 ng/ml versus 17.1 +/- 10.1 ng/ml, p less than 0.05; 0.52 +/- 0.44 versus 0.82 +/- 0.62, p less than 0.05). Six groups were formed according to HAL dose (number per group): 10 mg/day (6); 20 (11); 30 (11); 40 (4); 50 (3); and 60 (3). No significant differences were found in age, weight and dose/weight. In each dose group, HAL plasma levels were generally higher in the Chinese patients than in the non-Chinese patients, though significance was only detected in the 30 mg group (26.1 +/- 7.0 ng/ml versus 18.5 +/- 5.1 ng/ml, p = 0.035) and a slight trend in the 40 mg group (36.0 +/- 15.0 ng/ml versus 23.5 +/- 10.4 ng/ml, p = 0.074). RHAL/HAL ratios were generally lower in the Chinese patients than in the non-Chinese patients, with a strong trend toward the significance level in the 20 mg and 30 mg groups (0.22 +/- 0.13 versus 0.58 +/- 0.57, p = 0.066 and 0.43 +/- 0.26 versus 0.71 +/- 0.34, p = 0.062). This study further suggests the possibility of different metabolic rates between Chinese and non-Chinese patients. Possible differences in the enzyme systems which relate to the metabolism of HAL and RHAL between Chinese and non-Chinese populations are discussed.


[Effect of transfection of microRNA-146a on expression of tumor necrosis factor-a in alveolar macrophages].
To observe the effect of transfected microRNA-146a (miR-146a) on expression of tumor necrosis factor-alpha ( TNF-alpha ) in alveolar macrophages, and to analyze its regulatory mechanism in the inflammatory response of alveolar macrophages. Cy.11113 labeled with 25, 50, 100 nmol/L of Pre-miR", respectively, were transfected into rat alveolar macrophages NR8383 cultured in vitro. The highest transfection efficiency was selected to he the experimental concentration. NR8383 cells were divided into two groups: transfected group was tranfected with 50 nmol/L Pre-miR1111 miR-146a precursor, and control group with SO nmol/L Cym3 labeled Pre-miR1" as the negative control. The mRNA expression of miR-146a of cells was detected hy real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Then cells were stimulated with lipopolysaccharide (LPS, 1 mg/L) for 6 hours. The production of TNF-alpha protein in the supernatant of cells was assayed by enzyme-linked immunosorhent assay (ELISA) , and the expression of TNF-alpha mRNA of cells was detected hy RT-qPCR. Transfection rate was highest in the 50 nmol/L Cy11113 labeled Pre-miR"' cells, and it reached 80%. Compared with control group (set at 1), the expression of miR-146a increased by (24.55 ±6.14) folds in transfected alveolar marrophages (P<0.01). After the cells were stimulated with LPS, the production of TNF-alpha protein (ng/L) in the supernatant of cell was decreased from 616.6 ± 42.3 to 211.5 ± 30.4 (P<0.01), and the expression of TNF-alpha mRNA was decreased by (47 ± 6) % (P<0.05) in transfected alveolar macrophages when compared with that of the control. Transfection alveolar macrophages with miR-146a precursors could down-regulate the expression of TNF-alpha. It is therefore suggests that up-regulation of miR-146a can inhibit inflammatory responses as induced hy LPS, in alveolar macrophages.


Anisotropic polyhedral self-assembly of Ag-CNT nanocomposites.
We report the unique assembling behavior of Ag NP supported CNT nanocomposites. Initially Ag NPs were precipitated homogeneously on the walls of SDS-coated CNTs by a NaBH4 chemical reduction and/or photoreduction directly in an aqueous solution. An additional Ag source was subsequently added into the Ag-CNT dispersion and Ag was further reduced using hydroxylamine in a weakly alkaline condition. The morphology of the resulting Ag-CNT nanocomposites strongly depended on the Ag+ ion concentration. Interestingly, an anisotropic polyhedral self-assembly of Ag-CNT nanocomposites was observed when the Ag concentration was increased to 0.1 M (real concentration).


Deposition of the membrane attack complex of complement in bullous pemphigoid.
Bullous pemphigoid is associated with deposition of IgG and C3 at the dermal-epidermal junction. In order to see whether complement activation in bullous pemphigoid resulted in deposition of membrane attack complex (MAC) at the basement membrane zone, skin biopsies from patients with bullous pemphigoid were examined using a direct immunofluorescence technique. By employing a monoclonal antibody to a neoantigen of C9, the MAC was demonstrated in linear pattern at the basement membrane zone. These deposits were seen in both involved and uninvolved skin but the amount of MAC was greater in involved skin as judged by intensity of staining. Stippled deposits of MAC were also present in or around epidermal basal cells. The MAC could be generated in vitro by reaction of normal plasma with antibasement membrane antibody bound to sections of monkey esophagus. The IgG antibody activated complement and this complement activation proceeded all the way to the terminal step.


Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.
Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.


Effect of using disposable polyethylene bag as a probe cover or finger cover in pulse oximetry.
Consumer-grade pulse oximeters are used to monitor blood oxygen levels (SpO2) at home. Sharing a pulse oximeter with family members in isolation centers or home isolation due to COVID-19 may increase the chances of cross-infection. We aimed to find if using commonly available disposable polyethylene covers either on the finger and/or on the pulse oximeter provides the same reading of SpO2 or not. Two operators measured SpO2 on 10 healthy subjects with three randomly selected pulse oximeters. Six types of commonly available polythene bags (transparent, translucent, and opaque) were used to cover the fingers and/or device. After measuring the baseline SpO2 (i.e., without using covers), the measurements were taken with a covered finger, and/or covered oximeter probe. The mean age of the research participants (five male, five female) was 23.9 ± 5.11 years. Perfusion index was 9.12 ± 1.63 (males 9.6 ± 1.42, females 8.64 ± 1.85, P = 0.38). Black opaque polyethylene bag as finger or probe cover did not detect any signal. There was no difference in SpO2 reading when a pulse oximeter probe is covered, and/or a finger is covered. There was excellent inter-observer and inter-device agreement. Commonly available transparent and translucent polyethylene plastic bags may be used as finger or pulse oximeter cover without compromising the SpO2 reading. However, an opaque black plastic bag is not suitable for finger or probe cover. These easily available and cheap pulse oximeter covers may be used by multiple patients or family members in an emergency like the COVID-19 pandemic with the potential to prevent cross-infection.


Systemic lupus erythematosus and human endogenous retroviruses.
Abstract Human endogenous retroviruses (HERV) are known to be widely present in the human genome. Several investigations have suggested a possible etiological role of HERV in certain human disorders, including systemic lupus erythematosus (SLE). Here we review and discuss the possible role of HERV, especially HERV clone 4-1, in the onset of SLE, based on recent findings including our own data.


Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality.
Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin. Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels. Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.


Early-life risk factors and incidence of rhinitis: results from the European Community Respiratory Health Study--an international population-based cohort study.
Rhinitis is an increasingly common condition with a heavy health care burden, but relatively little is known about its risk factors. To examine the association between early-life factors and the development of rhinitis in the European Community Respiratory Health Study (ECRHS). In 1992-1994, community-based samples of 20-44-year-old people were recruited from 48 centers in 22 countries. On average, 8.9 years later, 28 centers reinvestigated their samples. Onset of rhinitis was reported by 8486 participants in interviewer-led questionnaires. Cox regression was used to assess independent predictors of rhinitis at ages ≤5, 6-10, 11-20, and ≥21 years. The crude lifelong incidence of rhinitis was 7.00/1000/year (men) and 7.95/1000/year (women) (P = .002). Women developed less rhinitis in later childhood (hazard ratios [HR], 0.63; 95% CI, 0.47-0.85) and more rhinitis in adulthood (HR, 1.36; 95% CI, 1.11-1.66) than did men. In atopic subjects, siblings were associated with lower risk of rhinitis throughout life (pooled HR, 0.94; 95% CI, 0.91-0.98 per 1 sibling). Early contact with children in the family or day care was associated with less incidence of rhinitis, predominantly before age 5 years (HR, 0.84; 95% CI, 0.72-0.99). Early childhood pets or growing up on a farm was associated with less incidence of rhinitis in adolescence (HR, 0.50; 95% CI, 0.37-0.68). Combining these factors showed evidence of a dose-response relationship (trend P = .0001). Gender is a strong risk factor for rhinitis, with age patterns varying according to atopic status. Protective effects of early contact with children and animals were suggested for incident rhinitis, with risk patterns varying by age window and atopic status.


The microbiome of New World vultures.
Vultures are scavengers that fill a key ecosystem niche, in which they have evolved a remarkable tolerance to bacterial toxins in decaying meat. Here we report the first deep metagenomic analysis of the vulture microbiome. Through face and gut comparisons of 50 vultures representing two species, we demonstrate a remarkably conserved low diversity of gut microbial flora. The gut samples contained an average of 76 operational taxonomic units (OTUs) per specimen, compared with 528 OTUs on the facial skin. Clostridia and Fusobacteria, widely pathogenic to other vertebrates, dominate the vulture's gut microbiota. We reveal a likely faecal-oral-gut route for their origin. DNA of prey species detectable on facial swabs was completely degraded in the gut samples from most vultures, suggesting that the gastrointestinal tracts of vultures are extremely selective. Our findings show a strong adaption of vultures and their bacteria to their food source, exemplifying a specialized host-microbial alliance.


¹³C NMR-distance matrix descriptors: optimal abstract 3D space granularity for predicting estrogen binding.
An improved three-dimensional quantitative spectral data-activity relationship (3D-QSDAR) methodology was used to build and validate models relating the activity of 130 estrogen receptor binders to specific structural features. In 3D-QSDAR, each compound is represented by a unique fingerprint constructed from (13)C chemical shift pairs and associated interatomic distances. Grids of different granularity can be used to partition the abstract fingerprint space into congruent "bins" for which the optimal size was previously unexplored. For this purpose, the endocrine disruptor knowledge base data were used to generate 50 3D-QSDAR models with bins ranging in size from 2 ppm × 2 ppm × 0.5 Å to 20 ppm × 20 ppm × 2.5 Å, each of which was validated using 100 training/test set partitions. Best average predictivity in terms of R(2)test was achieved at 10 ppm ×10 ppm × Z Å (Z = 0.5, ..., 2.5 Å). It was hypothesized that this optimum depends on the chemical shifts' estimation error (±4.13 ppm) and the precision of the calculated interatomic distances. The highest ranked bins from partial least-squares weights were found to be associated with structural features known to be essential for binding to the estrogen receptor.


To Lighten the Burden of Cure: Thyroid Disease in Long-Term Survivors After TBI Conditioning for Paediatric ALL.
Thyroid disorders are well-studied after allogeneic haematopoietic stem cell transplantation (HSCT) following total body irradiation (TBI)-based conditioning, occurring in 15-30% of paediatric survivors. The toxic effect of TBI is known but data on the role of immunological dysregulation (ID) and chronic graft-versus-host-disease (cGvHD) are scarce. We studied functional and structural thyroid disorders in 97 paediatric ALL patients after TBI-based HSCT, assessing their correlation with patient/transplant characteristics including cGvHD, prolonged immunosuppression and ID. The 10- and 15-year cumulative incidence (CI) of functional disorders was 50 and 60%. Univariate analysis revealed TBI in 6 vs. 8 fractions (p = 0.01), an interval between ALL diagnosis and HSCT <1 year (p = 0.038), and the application of ATG (p = 0.044) as risk factors. The 10- and 15-year CI of structural disorders was 60 and 80%. No correlation between patient/transplant characteristics and structural disorders was observed. cGvHD, prolonged immunosuppression and additional radiotherapy were not associated with any thyroid disease. We observed a significant correlation between ID and the development of thyroid dysfunction in patients with structural changes (10-year CI: 77% for patients with ID vs. 56% without ID, p = 0.02). The impact of our results on thyroid follow-up evaluations and the significance of hormonal replacement therapy are discussed.


Antibacterial activity and action target of phenyllactic acid against Staphylococcus aureus and its application in skim milk and cheese.
Phenyllactic acid (PLA) has been demonstrated to possess antibacterial activity and capacity to prolong food shelf life. However, studies on the performance of PLA in inhibiting Staphylococcus aureus and its effectiveness when applied to dairy products are largely lacking. Here, antibacterial activity (planktonic and biofilm states) of PLA against S. aureus CICC10145 (S. aureus_45) were investigated. The results showed that PLA inhibited growth of S. aureus_45 and formation of S. aureus_45 biofilm. Next, the antibacterial action target of PLA was uncovered from both physiological and phenotypic perspectives. The results showed that PLA decreased cell metabolic activity and cell viability, damaged cell membrane integrity, triggered leakage of intracellular contents (DNA, proteins, and ATP), and caused oxidative stress damage and morphological deformation of S. aureus_45. In practical application, the antibacterial activity of PLA against S. aureus_45 cells was further confirmed in skim milk and cheese as dairy food models, and the antibacterial effects can be adequately maintained during storage for 21 d, at least at 4°C. These findings suggested that PLA could be a potential candidate for controlling S. aureus outgrowth in dairy foods.


Response of runoff towards land use changes in the Yellow River Basin in Ningxia, China.
Since the Yellow River is a main source of water in Ningxia China, maintaining its healthy ecological environment is vital to Ningxia and the neighboring areas. Changes of land use caused by human activities such as population growth, urbanizing process, and industrial and mining construction would affect the balance and cycle of water in the Basin. Therefore, investigating hydrological responses of land use changes can provide insights into the characteristics and evolution of runoff the Yellow River Basin in the Ningxia section. This has imperative and practical significance to the rational use, allocation, and planning of water resources in a changing environment. In this paper, we analyzed the meteorological and hydrological elements of changing characteristics of the Yellow River Basin in the Ningxia section. Then we selected a distribution-based hydrology model of SWAT in combination with GIS to simulate annual and monthly runoff under different land use scenarios. Finally, we analyzed the influence caused by the changes of land use on runoff. We concluded that it is appropriate to lay a decision-making foundation to manage water resources of the Yellow River Basin in the Ningxia section.


MafB-restricted local monocyte proliferation precedes lung interstitial macrophage differentiation.
Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C+ classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206+ IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo.


Type VI collagen is associated with microfibrils and oxytalan fibers in the extracellular matrix of periodontium, mesenterium and periosteum.
Type VI collagen was immunolocalized in several soft connective tissues at the light and electron microscopic level. Positive labeling was found in all tissues examined, periodontal ligament, gingiva, mesenterium and periosteum. The labeled structures could be divided into 2 categories: microfibrils intermingling with collagen fibrils, and those that formed bundles (oxytalan fibres and elastin-associated microfibrils). Control sections incubated with antibody preabsorbed to purified type VI collagen, or with non-immune antibody, proved to be negative. Our observations indicate that the structural organization of type VI collagen varies from small microfibrillar structures associated with the collagen and elastin fibre systems to highly ordered parallel arrays of oxytalan bundles.


A purified Bacillus thuringiensis crystal protein with therapeutic activity against the hookworm parasite Ancylostoma ceylanicum.
Crystal (Cry) proteins produced by the soil bacterium Bacillus thuringiensis (Bt) are harmless to vertebrates, but they are highly toxic to insects and nematodes. Their value in controlling insects that destroy crops and transmit human diseases is well established. Although it has recently been demonstrated that a few individual Bt Cry proteins, such as Cry5B, are toxic to a wide range of free-living nematodes, the potential activity of purified Cry proteins against parasitic nematodes remains largely unknown. We report here studies aimed at characterizing in vitro and in vivo anthelminthic activities of purified recombinant Cry5B against the hookworm parasite Ancylostoma ceylanicum, a bloodfeeding gastrointestinal nematode for which humans are permissive hosts. By using in vitro larval development assays, Cry5B was found to be highly toxic to early stage hookworm larvae. Exposure of adult A. ceylanicum to Cry5B was also associated with significant toxicity, including a substantial reduction in egg excretion by adult female worms. To demonstrate therapeutic efficacy in vivo, hamsters infected with A. ceylanicum were treated with three daily oral doses of purified Cry5B, the benzimidazole anthelminthic mebendazole, or buffer. Compared with control (buffer-treated) animals, infected hamsters that received Cry5B showed statistically significant improvements in growth and blood hemoglobin levels as well as reduced worm burdens that were comparable to the mebendazole-treated animals. These data demonstrate that Cry5B is highly active in vitro and in vivo against a globally significant nematode parasite and that Cry5B warrants further clinical development for human and veterinary use.


Results of operative treatment of fractures of the posterior wall of the acetabulum.
The purpose of this study was to determine the clinical outcome in patients in whom a displaced fracture of the posterior wall of the acetabulum had been treated by open reduction and internal fixation. One hundred patients who had had open reduction and internal fixation of an unstable unilateral fracture of the posterior wall of the acetabulum were studied. Ninety-four patients were assessed at a mean of five years (range, two to fourteen years) after the injury. Six patients with a poor result were followed for less than two years. The functional outcome was evaluated with use of the clinical grading system adopted by Letournel and Judet with incorporation of modifications by Matta. Patient, fracture, and radiographic variables were analyzed to identify possible associations with functional outcome. The reduction of the fracture, as determined with plain radiography, was graded as anatomic in ninety-seven patients and as imperfect in three. The clinical outcome at the time of final follow-up was graded as excellent in fifty-five patients, very good in twenty-five, good in nine, fair in one, and poor in ten. The radiographic result was excellent in eighty-one patients, good in five, fair in four, and poor in ten. There was a strong association between the clinical outcome and the final radiographic grade. Variables identified as risk factors for an unsatisfactory clinical result included a delay of greater than twelve hours before reduction of an associated hip dislocation, an age of fifty-five years or older at the time of injury, intra-articular comminution, and osteonecrosis. The uncomplicated radiographic appearance and relatively simple operative approach for fractures of the posterior acetabular wall belie the risk of poor results. Prompt reduction of an associated hip dislocation is imperative. Fractures in elderly patients and those with extensive comminution are more likely to have a poor clinical result. However, a high likelihood of a long-term good-to-excellent result can be expected following anatomic reduction and internal fixation of these fractures.


Hereditary and histologic characteristics of the CF1/b cac mouse cataract model.
A substrain of mice originating from the CF1 strain (an outbred colony) reared at Osaka Prefecture University (CF1/b cac mice) develops cataracts beginning at 14 d old. Affected mice were fully viable and fertile and had developed cataracts by 22 d of age. The incidence of cataracts did not differ between male and female mice. Histologically, 14-wk-old CF1/b cac mice showed vacuolated lens epithelial cells, swollen lens fibers, many pyknotic nuclei, and vacuolation of the lens cortex. To elucidate the mode of inheritance, we analyzed heterozygous mutants hybrids generated from CF1/b cac and wildtype BALB/c mice and the offspring of the backcrossed heterozygous mutants. None of the heterozygous mutants was affected, but the ratio of affected to unaffected mice was 1:3 among the offspring of the heterozygous mutants. The initial genomewide screen of 20 affected backcrossed offspring (CF1/b cac × [CF1/b cac × BALB/c]) indicated that the mutant gene resides on chromosome 16. For further mapping, we used affected progeny of CF1/b cac × (CF1/b cac × MSM/Ms) mice. We concluded that the cataracts in CF1/b cac mice are inherited through an autosomal recessive mutation and that the mutant gene is located on mouse chromosome 16 between D16Mit5 and D16Mit92 and between D16Mit92 and D16Mit201. The mapping of the mutant gene of the CF1/b cac mice to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the CF1/b cac phenotype.


L-kynurenine: its synthesis and possible regulatory function in brain.
One pathway by which tryptophan is metabolized in the brain as well as in the periphery is through cleavage of the indole ring to formylkynurenine and then kynurenine. Indoleamine-2,3-dioxygenase, the enzyme that catalyzes this cleavage, and kynurenine are distributed all across the different anatomic regions of brain. Approximately 40% of the kynurenine in brain is synthesized there, the remainder having come from plasma. Tryptophan loading, which has been used both experimentally and therapeutically as a means of increasing tryptophan conversion to serotonin, also increases kynurenine formation in the brain and in the periphery. Because of the formation of kynurenine, which competes for cerebral transport and cellular uptake of L-tryptophan, and because of substrate inhibition on tryptophan hydroxylase, excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.


A general allometric and life-history model for cellular differentiation in the transition to multicellularity.
The transition from unicellular, to colonial, to larger multicellular organisms has benefits, costs, and requirements. Here we present a model inspired by the volvocine green algae that explains the dynamics involved in the unicellular-multicellular transition using life-history theory and allometry. We model the two fitness components (fecundity and viability) and compare the fitness of hypothetical colonies of different sizes with varying degrees of cellular differentiation to understand the general principles that underlie the evolution of multicellularity. We argue that germ-soma separation may have evolved to counteract the increasing costs and requirements of larger multicellular colonies. The model shows that the cost of investing in soma decreases with size. For lineages such as the Volvocales, as reproduction costs increase with size for undifferentiated colonies, soma specialization benefits the colony indirectly by decreasing such costs and directly by helping reproductive cells acquire resources for their metabolic needs. Germ specialization is favored once soma evolves and takes care of vegetative functions. To illustrate the model, we use some allometric relationships measured in Volvocales. Our analysis shows that the cost of reproducing an increasingly larger group has likely played an important role in the transition to multicellularity and cellular differentiation.


The effect of gestational age on angiogenic gene expression in the rat placenta.
The placenta plays a central role in determining the outcome of pregnancy. It undergoes changes during gestation as the fetus develops and as demands for energy substrate transfer and gas exchange increase. The molecular mechanisms that coordinate these changes have yet to be fully elucidated. The study performed a large scale screen of the transcriptome of the rat placenta throughout mid-late gestation (E14.25-E20) with emphasis on characterizing gestational age associated changes in the expression of genes involved in angiogenic pathways. Sprague Dawley dams were sacrificed at E14.25, E15.25, E17.25 and E20 (n = 6 per group) and RNA was isolated from one placenta per dam. Changes in placental gene expression were identified using Illumina Rat Ref-12 Expression BeadChip Microarrays. Differentially expressed genes (>2-fold change, <1% false discovery rate, FDR) were functionally categorised by gene ontology pathway analysis. A subset of differentially expressed genes identified by microarrays were confirmed using Real-Time qPCR. The expression of thirty one genes involved in the angiogenic pathway was shown to change over time, using microarray analysis (22 genes displayed increased and 9 gene decreased expression). Five genes (4 up regulated: Cd36, Mmp14, Rhob and Angpt4 and 1 down regulated: Foxm1) involved in angiogenesis and blood vessel morphogenesis were subjected to further validation. qPCR confirmed late gestational increased expression of Cd36, Mmp14, Rhob and Angpt4 and a decrease in expression of Foxm1 before labour onset (P<0.0001). The observed acute, pre-labour changes in the expression of the 31 genes during gestation warrant further investigation to elucidate their role in pregnancy.


Stimuli-Responsive Polymeric Systems for Controlled Protein and Peptide Delivery: Future Implications for Ocular Delivery.
Therapeutic proteins and peptides have become notable in the drug delivery arena for their compatibility with the human body as well as their high potency. However, their biocompatibility and high potency does not negate the existence of challenges resulting from physicochemical properties of proteins and peptides, including large size, short half-life, capability to provoke immune responses and susceptibility to degradation. Various delivery routes and delivery systems have been utilized to improve bioavailability, patient acceptability and reduce biodegradation. The ocular route remains of great interest, particularly for responsive delivery of macromolecules due to the anatomy and physiology of the eye that makes it a sensitive and complex environment. Research in this field is slowly gaining attention as this could be the breakthrough in ocular drug delivery of macromolecules. This work reviews stimuli-responsive polymeric delivery systems, their use in the delivery of therapeutic proteins and peptides as well as examples of proteins and peptides used in the treatment of ocular disorders. Stimuli reviewed include pH, temperature, enzymes, light, ultrasound and magnetic field. In addition, it discusses the current progress in responsive ocular drug delivery. Furthermore, it explores future prospects in the use of stimuli-responsive polymers for ocular delivery of proteins and peptides. Stimuli-responsive polymers offer great potential in improving the delivery of ocular therapeutics, therefore there is a need to consider them in order to guarantee a local, sustained and ideal delivery of ocular proteins and peptides, evading tissue invasion and systemic side-effects.


[How I treat ... dyslipidemia according to the cardiovascular risk profile].
The new guidelines from the European Atherosclerosis Society and the European Society of Cardiology include a number of new items. Here we demonstrate their application in several different clinical examples. We focus on the 4 items most pertinent for medical practice: 1) the stratification of risk of cardiovascular disease into 4 categories ('very high', 'high', 'moderate' and 'low risk'), involving--for primary prevention cases--the use of the SCORE table, which has been calibrated for Belgium and where the risk can be adjusted according to HDL cholesterol and the presence of other risk factors; 2) the choice of more stringent therapeutic targets for LDL cholesterol (< 70 mg/dl for 'very high' risk patients, 100 mg/dl for 'high' risk patients and 115 mg/dl for patients at 'moderate' risk); 3) the choice of other therapeutic targets (non-HDL cholesterol and apolipoprotein B levels) for patients at 'very high' or 'high' risk with combined dyslipidaemia; and 4) follow-up of lipid parameters and muscular and hepatic enzymatic profiles.