Interaction of fumonisin B(1) and aflatoxin B(1) in a short-term carcinogenesis model in rat liver.
The co-existence of the fumonisin and aflatoxin mycotoxins in corn merited studies to investigate their possible synergistic toxicological and carcinogenic effects. When utilising a short-term carcinogenesis model in rat liver, both the compounds exhibited slow cancer initiating potency as monitored by the induction of foci and nodules stained positively for the placental form of gluthatione-S-transferase (GSTP(+)). However, when rats were treated in a sequential manner with AFB(1) and FB(1) the number and size of GSTP(+) lesions significantly increased as compared to the separate treatments. Histopathological analyses indicated that the individual treatments showed far less toxic effects, including occasional hepatocytes with dysplastic nuclei, oval cell proliferation and, in the case of FB(1), a few apoptotic bodies in the central vein regions. The sequential treatment regimen induced numerous foci and dysplastic hepatocyte nodules, and with oval cells extending from the periportal regions into the centrilobular regions. This would imply that, in addition to the cancer promoting activity of FB(1) of AFB(1)-initiated hepatocytes, the AFB(1) pre-treatment enhanced the FB(1) initiating potency, presumably by rendering the liver more susceptible to the toxic effects of FB(1). The co-occurrence of AFB(1) and FB(1) in corn consumed as a staple diet could pose an increased risk and should be included in establishing risk assessment parameters in humans.


Ethnopharmacology, phytochemistry and biological activity of Erodium species: A review.
Erodium spp. is a genus that can be found in all continents that has been traditionally used in folk medicine to treat many diseases such as hemorrhage, dermatological disorders, indigestion, and inflammatory diseases. Moreover, Erodium leaves have been used for the preparation of salads, omelets, sandwiches, sauces and soups, among other food products. The objective of this review was to show the recent and relevant studies about extraction of bioactive compounds, the phytochemical characterization, the potential biological activities and toxicological evidence reported in both in vitro and in vivo studies from Erodium spp. In addition, the use of Erodium spp. as natural compounds against the development of diseases were also showed. This review highlights the traditional use of Erodium species in several countries as a therapeutic agent to treat several diseases (such as constipation, dermatological disorders, diabetes, indigestion, urinary inflammations, and as carminative agent), the factors influencing the extraction of bioactive compounds (mainly species and solvent composition on phenolic compounds) and phytochemical profile (presence of essential oils and alkaloids), the scientific evidence about its anti-inflammatory, antimicrobial (against both spoilage and pathogenic microorganisms), antiviral and other health-related activities (anti-protozoal and anti-viral activity) as well as the toxicological evidence. Erodium spp. is a relevant source of compounds with antioxidant, antimicrobial, and biological activity, which support its potential exploration in pharmacological and food area. Major efforts are necessary to advance the knowledge about Erodium genus regarding the relation between traditional use and scientific evidence, optimization of extraction conditions, the influence on biological mechanisms at animal and clinical levels, and bioaccessibility and bioavailability of bioactive compounds.


Strain improvement of Trichoderma spp. through two-step protoplast fusion for cellulase production enhancement.
Fungal protoplast fusion is an approach to introduce novel characteristics into industrially important strains. Cellulases, essential enzymes with a wide range of biotechnological applications, are produced by many species of the filamentous fungi Trichoderma. In this study, a collection of 60 natural isolates were screened for Avicel and carboxymethyl cellulose degradation, and two cellulase producers of Trichoderma virens and Trichoderma harzianum were used for protoplast fusion. One of the resulting hybrids with improved cellulase activity, C1-3, was fused with the hyperproducer Trichoderma reesei Rut-C30. A new selected hybrid, F7, was increased in cellulase activity 1.8 and 5 times in comparison with Rut-C30 and C1-3, respectively. The increases in enzyme activity correlated with an upregulation of the cellulolytic genes cbh1, cbh2, egl3, and bgl1 in the parents. The amount of mRNA of cbh1 and cbh2 in F7 resembled that of Rut-C30 while the bgl1 mRNA level was similar to that of C1-3. AFLP (amplified fragment length polymorphism) fingerprinting and GC-MS (gas chromatography - mass spectrometry) analysis represented variations in parental strains and fusants. In conclusion, the results demonstrate that a 3-interspecific hybrid strain was isolated, with improved characteristics for cellulase degradation and showing genetic polymorphisms and differences in the volatile profile, suggesting reorganizations at the genetic level.


Grape seed and skin extract protects against bleomycin-induced oxidative stress in rat lung.
Lung fibrosis is a common side effect of the chemotherapeutic agent bleomycin and current evidence suggests that reactive oxygen species play a key role in the development of lung injury. We examined whether grape seed and skin extract (GSSE), a polyphenolic mixture exhibiting antioxidant properties, is able to protect against bleomycin-induced lung oxidative stress and injury. Rats were pre-treated during three weeks either with vehicle (ethanol 10% control) or GSSE (4g/kg), then administered with a single high dose bleomycin (15mg/kg) at the 7th day. Bleomycin increased lung lipoperoxidation, carbonylation and decreased antioxidant enzyme activities as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Bleomycin also induced copper depletion from the lung and iron accumulation within the lung, but had no effect on either zinc nor manganese. Correlatively bleomycin decreased the copper associated enzyme tyrosinase, increased the zinc dependent lactate dehydrogenase (LDH) and did not affect the manganese dependent glutamine synthetase. GSSE efficiently counteracted almost all bleomycin-induced oxidative stress, biochemical and morphological changes of lung tissue. Data suggest that GSSE exerts potent antioxidant properties that could find potential application in the protection against bleomycin-induced lung fibrosis.


Increased 4-hydroxy-2-nonenal-induced proteasome dysfunction is correlated with cardiac damage in streptozotocin-injected rats with isoproterenol infusion.
Increase in 4-hydroxy-2-nonenal (4HNE) due to oxidative stress has been observed in a variety of cardiac diseases such as diabetic cardiomyopathy. 4HNE exerts a damaging effect in the myocardium by interfering with subcellular organelles like mitochondria by forming adducts. Therefore, we hypothesized that increased 4HNE adduct formation in the heart results in proteasome inactivation in isoproterenol (ISO)-infused type 1 diabetes mellitus (DM) rats. Eight-week-old male Sprague Dawley rats were injected with streptozotocin (STZ, 65 mg kg(-1) ). The rats were infused with ISO (5 mg kg(-1) ) for 2 weeks by mini pumps, after 8 weeks of STZ injection. We studied normal control (n = 8) and DM + ISO (n = 10) groups. Cardiac performance was assessed by echocardiography and Millar catheter at the end of the protocol at 20 weeks. Initially, we found an increase in 4HNE adducts in the hearts of the DM + ISO group. There was also a decrease in myocardial proteasomal peptidase (chymotrypsin and trypsin-like) activity. Increases in cardiomyocyte area (446 ± 32·7 vs 221 ± 10·83) (µm(2) ), per cent area of cardiac fibrosis (7·4 ± 0·7 vs 2·7 ± 0·5) and cardiac dysfunction were also found in DM + ISO (P < 0·05) relative to controls. We also found increased 4HNE adduct formation on proteasomal subunits. Furthermore, reduced aldehyde dehydrogenase 2 activity was observed in the myocardium of the DM + ISO group. Treatment with 4HNE (100 μM) for 4 h on cultured H9c2 cardiomyocytes attenuated proteasome activity. Therefore, we conclude that the 4HNE-induced decrease in proteasome activity may be involved in the cardiac pathology in STZ-injected rats infused with ISO. Copyright © 2016 John Wiley & Sons, Ltd.


Glycerol incorporation into brain lipids in rat pups born to ethanol-intoxicated dams.
The incorporation of labeled glycerol into glycerolipid of rat brain was influenced by the age of the animal (2-month-old vs. newborn); indeed, 12 min after the administration, diglyceride was the most heavily labeled glycerolipid in the newborn brain, whereas the labeling of glycerophospholipid was highest in the adult. Various amounts of ethanol (0% to 36% of total energy intake) were administered to pregnant female rats, and the brains of their pups were examined for the ability to incorporate labeled glycerol into glycerolipid. The radioactivity incorporated into lipid diminished with increasing the amounts of alcohol consumed. The labeling pattern of lipid classes was also influenced; indeed, the radioactivity of diglyceride decreased markedly, whereas that of triglyceride and glycerophospholipid was affected to a lower degree. The distribution of radioactivity among different phospholipids also varied with age; on a percent basis, phosphatidylcholine was labeled less and phosphatidylinositol was labeled more in the newborn than in the adult. Ethanol influenced the pattern of glycerophospholipid labeling, increasing the radioactivity of phosphatidylserine and decreasing that of phosphatidylinositol.


Effects of limiting anterior displacement of the center of foot pressure on anticipatory postural control during bilateral shoulder flexion.
In bilateral shoulder flexion with the arms moving from the sides of the body to the horizontal level while standing, no preceding activation of the triceps surae (TS) with respect to focal muscles has been found. Considering that preceding activation would offer a useful indicator of anticipatory postural control, it was attempted to induce preceding activation by limiting the anterior displacement range of the center of foot pressure in the anteroposterior direction (CoPap). Subjects were 13 healthy young adults. The 50% anterior range of CoPap displacement caused by shoulder flexion was calculated, and the floor inclined by the subject's weight when CoPap extended beyond that range. Subjects were instructed not to incline the floor during shoulder flexion. Under the limitation condition, the ankle and knee joints plantarflexed and extended at 1.1°, respectively, with no hip movement; that is, the whole body inclined backward by pivoting at the ankle. This limitation resulted in preceding muscle activation of TS as well as erector spinae and biceps femoris, and no significant differences in onset time were seen between these muscles. These results demonstrated that by limiting CoPap anterior displacement, preceding activation of TS could be induced with backward inclination of the whole body.


Cloning, expression, and characterization of a wide-pH-range stable phosphite dehydrogenase from Pseudomonas sp. K in Escherichia coli.
A phosphite dehydrogenase gene (ptdhK) consisting of 1,011-bp nucleotides which encoding a peptide of 336 amino acid residues was cloned from Pseudomonas sp. K. gene ptdhK was expressed in Escherichia coli BL21 (DE3) and the corresponding recombinant enzyme was purified by metal affinity chromatography. The recombinant protein is a homodimer with a monomeric molecular mass of 37.2 kDa. The specific activity of PTDH-K was 3.49 U mg(-1) at 25 °C. The recombinant PTDH-K exhibited maximum activity at pH 3.0 and at 40 °C and displayed high stability within a wide range of pHs (5.0 to 10.5). PTDH-K had a high affinity to its natural substrates, with K (m) values for sodium phosphite and NAD of 0.475 ± 0.073 and 0.022 ± 0.007 mM, respectively. The activity of PTDH-K was enhanced by Na(+), NH (4) (+) , Mg(2+), Fe(2+), Fe(3+), Co(2+), and EDTA, and PTDH-K exhibited different tolerance to various organic solvents.


Staphylococcal septic arthritis presenting as acute flare of pseudogout: clinical, pathological and arthroscopic findings with a review of the literature.
A patient with primary hyperparathyroidism and known pseudogout presented with an acute flare of the right knee. Gram stain was negative, and many intracellular calcium pyrophosphate dihydrate (CPPD) crystals were seen by both compensated polarized light and transmission electron microscopy. Cultures grew Staphylococcus aureus; the joint was probably seeded by an antecedent skin infection, with enzymatic "strip mining" precipitating acute pseudogout. The patient was refractory to therapy with oxacillin, naproxen, intravenous colchicine, and closed drainage. Arthroscopic debridement with insertion of drainage tubes led to rapid improvement, and offers an alternative to arthrotomy in septic knee arthritis unresponsive to closed drainage.


Recurrent meningitis due to a congenital fistula of the stapedial footplate.
A rare case of a congenital fistula of the stapes footplate, in a 10-year-old girl, resulting in recurrent meningitis, is reported. A full ENT examination and a high index of suspicion, is essential if the diagnosis is to be made. Exploratory tympanotomy should be considered on clinical grounds, even if a high resolution CT scan of the temporal bones does not show any anomalies, in order to ascertain the definite diagnosis of a fistula and to seal it permanently.


The effect of left ventricular electrical delay on AV optimization for cardiac resynchronization therapy.
The role of atrioventricular optimization (AVO) for cardiac resynchronization therapy (CRT) is controversial. Identifying subgroups that benefit from optimization is important to improve CRT outcomes. Pacing at sites of late electrical activation, as assessed by the QLV interval, improves remodeling with CRT. To evaluate whether pacing at sites of long left ventricular (LV) electrical delay increases the effectiveness of AVO. This substudy of the SMART-AV trial included 280 subjects who were randomized to either an electrogram-based AVO (SmartDelay) or nominal atrioventricular delay (120 ms). The QLV interval was defined as the time from the onset of QRS to the LV electrogram peak. CRT response was defined prospectively as a >15% reduction in left ventricular end systolic volume from implant to 6 months. The cohort was 68% men, with a mean age of 66 ± 11 years and LV ejection fraction of 28% ± 8%. Longer QLV durations were significantly associated with CRT response (P < .01) for the entire cohort. Moreover, the benefit of AVO increased as QLV prolonged. At the longest QLV quartile, there was more than a 6-fold increase in the likelihood of a remodeling response compared with nominal atrioventricular delays. Baseline electrical dyssynchrony, as measured by the QLV interval, predicted CRT response. At long QLV intervals, AVO can increase the likelihood of structural response to CRT. AVO and QLV optimized that LV lead location may work synergistically to maximize CRT response.


Comprehensive Analysis of Clinical Logistic and Machine Learning-Based Models for the Evaluation of Pulmonary Nodules.
Over the years, multiple models have been developed for the evaluation of pulmonary nodules (PNs). This study aimed to comprehensively investigate clinical models for estimating the malignancy probability in patients with PNs. PubMed, EMBASE, Cochrane Library, and Web of Science were searched for studies reporting mathematical models for PN evaluation until March 2020. Eligible models were summarized, and network meta-analysis was performed on externally validated models (PROSPERO database CRD42020154731). The cut-off value of 40% was used to separate patients into high prevalence (HP) and low prevalence (LP), and a subgroup analysis was performed. A total of 23 original models were proposed in 42 included articles. Age and nodule size were most often used in the models, whereas results of positron emission tomography-computed tomography were used when collected. The Mayo model was validated in 28 studies. The area under the curve values of four most often used models (PKU, Brock, Mayo, VA) were 0.830, 0.785, 0.743, and 0.750, respectively. High-prevalence group (HP) models had better results in HP patients with a pooled sensitivity and specificity of 0.83 (95% confidence interval [CI]: 0.78-0.88) and 0.71 (95% CI: 0.71-0.79), whereas LP models only achieved pooled sensitivity and specificity of 0.70 (95% CI: 0.60-0.79) and 0.70 (95% CI: 0.62-0.77). For LP patients, the pooled sensitivity and specificity decreased from 0.68 (95% CI: 0.57-0.78) and 0.93 (95% CI: 0.87-0.97) to 0.57 (95% CI: 0.21-0.88) and 0.82 (95% CI: 0.65-0.92) when the model changed from LP to HP models. Compared with the clinical models, artificial intelligence-based models have promising preliminary results. Mathematical models can facilitate the evaluation of lung nodules. Nevertheless, suitable model should be used on appropriate cohorts to achieve an accurate result.


Reimbursement Policies for Carotid Duplex Ultrasound that are Based on International Classification of Diseases Codes May Discourage Testing in High-Yield Groups.
To curb increasing volumes of diagnostic imaging and costs, reimbursement for carotid duplex ultrasound (CDU) is dependent on "appropriate" indications as documented by International Classification of Diseases (ICD) codes entered by ordering physicians. Historically, asymptomatic indications for CDU yield lower rates of abnormal results than symptomatic indications, and consensus documents agree that most asymptomatic indications for CDU are inappropriate. In our vascular laboratory, we perceived an increased rate of incorrect or inappropriate ICD codes. We therefore sought to determine if ICD codes were useful in predicting the frequency of abnormal CDU. We hypothesized that asymptomatic or nonspecific ICD codes would yield a lower rate of abnormal CDU than symptomatic codes, validating efforts to limit reimbursement in asymptomatic, low-yield groups. We reviewed all outpatient CDU done in 2011 at our institution. ICD codes were recorded, and each medical record was then reviewed by a vascular surgeon to determine if the assigned ICD code appropriately reflected the clinical scenario. CDU findings categorized as abnormal (>50% stenosis) or normal (<50% stenosis) were recorded. Each individual ICD code and group 1 (asymptomatic), group 2 (nonhemispheric symptoms), group 3 (hemispheric symptoms), group 4 (preoperative cardiovascular examination), and group 5 (nonspecific) ICD codes were analyzed for correlation with CDU results. Nine hundred ninety-four patients had 74 primary ICD codes listed as indications for CDU. Of assigned ICD codes, 17.4% were deemed inaccurate. Overall, 14.8% of CDU were abnormal. Of the 13 highest frequency ICD codes, only 433.10, an asymptomatic code, was associated with abnormal CDU. Four symptomatic codes were associated with normal CDU; none of the other high frequency codes were associated with CDU result. Patients in group 1 (asymptomatic) were significantly more likely to have an abnormal CDU compared to each of the other groups (P < 0.001, P < 0.001, P = 0.020, P = 0.002) and to all other groups combined (P < 0.001). Asymptomatic indications by ICD codes yielded higher rates of abnormal CDU than symptomatic indications. This finding is inconsistent with clinical experience and historical data, and we suggest that inaccurate coding may play a role. Limiting reimbursement for CDU in low-yield groups is reasonable. However, reimbursement policies based on ICD coding, for example, limiting payment for asymptomatic ICD codes, may impede use of CDU in high-yield patient groups.


Genetic aspects of animal reasoning.
This paper reviews the investigations of Prof. L. V. Krushinsky and his colleagues into the genetics of complex behaviors in mammals. The ability of animals to extrapolate the direction of a food stimulus movement was investigated in wild and domesticated foxes (including different fur-color mutants), wild brown rats, and laboratory rats and mice. Wild animals (raised in the laboratory) were shown to be superior to their respective domesticated forms on performance of the extrapolation task, especially in their scores for the first presentation, in which no previous experience could be used. Laboratory rats and mice demonstrated a low level of extrapolation performance. This means that only a few laboratory animals were capable of solving the task, i.e., the percentage of correct solutions was equivalent to chance. The brain weight selection program resulted in two mice strains with a 20% (90-mg) difference in brain weight. Ability to solve the extrapolation task was present in low-brain weight mice in generations 7-11 but declined with further selection. Investigation of extrapolation ability in mice with different chromosomal anomalies demonstrated that animals with Robertsonian translocations Rb(8,17) 1lem and Rb(8,17) 6Sic were capable of solving this task in a statistically significant majority of cases, while mice with fusion of other chromosomes, as well as CBA normal karyotype mice, performed no better than expected by chance. Mice with two types of partial trisomies and animals homo- and heterozygous for translocations were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)


Decreasing one-year mortality and hospitalization rates for heart failure in Sweden; Data from the Swedish Hospital Discharge Registry 1988 to 2000.
To investigate if improved treatment of coronary heart disease and hypertension, the major causes of chronic heart failure (CHF), in the last 20 years has had an impact on the incidence of CHF and survival. National Swedish registers on hospital discharges and cause-specific deaths were used to calculate age- and sex-specific trends and sex ratios for heart failure admissions and deaths. The study included all men and women 45 to 84 years old hospitalized for the first time for heart failure in 19 Swedish counties between 1988 and 2000, a mean annual population 2.9 million. A total of 156?919 hospital discharges were included. In 1988, a total of 267 men and 205 women per 100?000 inhabitants (age adjusted) were discharged for the first time with a principal diagnosis of heart failure. After 1993 a yearly decrease was observed, with 237 men and 171 women per 100?000 inhabitants discharged during 2000. The 30-day mortality decreased significantly. The decrease in 1-year mortality was more pronounced in the younger age groups, with a total reduction in mortality of 69% among men and 80% among women aged 45-54 years. The annual decrease was 9% among men and 10% among women aged 45-54 years (95% CI -7% to -12% and -6% to -14% respectively) and 4% among men and 5% among women (95% CI -4% to -5% for both) aged 75-84 years. The decrease in incidence and improved prognosis after a first hospitalization for heart failure coincides with the establishment of ACE-inhibitor therapy, the introduction of beta-blockers for treatment of heart failure, home-care programmes for heart failure, and more effective treatment and prevention of underlying diseases. Notwithstanding, despite considerable improvement, 1-year mortality after a first hospitalization for heart failure is still high.


Breast cancer vaccines: current research and future prospects.
Although the immune system can clearly recognize cancer cells, there is little evidence that it does so to any effective consequence in patients with advanced breast cancer. The possibility of effective control of micrometastatic disease remains but is unproven. The challenge for the clinician is to find ways to enhance the ability of a patient's own immune system to recognize and effectively target malignant cells. It is clear that there is no shortage of target antigens for immune cell recognition of breast cancer but it is less certain whether the route to an effective therapeutic strategy lies with enhanced recognition of an individual target or a more general route to enhanced immune cell activation.


Differences in age distribution in first and second waves of COVID-19 in eastern Uttar Pradesh, India.
Comparison of first and second waves of Coronavirus disease (COVID-19) showed varied differences including the peak and time distribution. Contrary to published reports of comparing two waves in India wherein the younger age group was affected more in the second wave in India; a secondary data analysis of around 0.5 million real-time reverse transcription-polymerase chain reaction tests conducted in COVID-19 diagnostic laboratory in eastern Uttar Pradesh, India showed an increase in positivity rate in older age groups in the second wave. The positivity rate among symptomatic cases was found to be three times higher in second wave compare to the first wave. Higher positivity rates were seen across older age groups, with a shift of 11 years in the mean age of positivity in the second wave compared to the first.


Modeling zero-inflated count series with application to occupational health.
A zero-inflated Poisson mixed autoregression model is presented for analyzing time series of count events with excess zeros. The model is motivated by the evaluation of a participatory ergonomics intervention intended to reduce manual handling workplace injuries over a specified time period. Random effects are introduced into the linear predictor of the model to account for serial correlation between successive observations. Parameter estimation is achieved by maximizing an appropriate log-likelihood function to obtain approximate residual maximum likelihood estimates. The method enables the evaluation of occupational intervention using population level aggregated count data series containing extra zeros.


Easily measurable adverse outcome indicators in a Veterans Affairs nursing home.
Indicator data were collected from October 1986 through April 1987 for 356 residents of the nursing home at the North Chicago, Illinois, Veterans Administration Medical Center. Measures of prevalence, incidence, and rates of change were studied for 17 adverse outcome indicators of four main types: death, undernutrition, skin breakdown, and loss of activities of daily living (eating, mobility, transfer, and toileting). Indicator values can be calculated from data routinely collected for administrative and other clinical purposes and can be used to help nursing home administrators monitor trends in the physical status of residents and to establish and track compliance with quality assurance goals.


Primed B cells present type-II collagen to T cells.
Development of type-II collagen (CII)-induced arthritis (CIA) is dependent on a T-cell mediated activation of autoreactive B cells. However, it is still unclear if B cells can present CII to T cells. To investigate the role of B cells as antigen-presenting cells (APCs) for CII, we purified B cells from lymph nodes of immunized and nonimmunized mice. These B cells were used as APC for antigen-specific T-cell hybridomas. B cells from naïve mice did present native, triple-helical, CII (nCII) but also ovalbumin (OVA) and denatured CII (dCII) to antigen-specific T-cell hybridomas. In addition, B cells primed with nCII or OVA, but not dCII, activated the antigen-specific T-cell hybridomas two to three times better than naïve B cells. We conclude that antigen-primed B cells have the capacity to process and present CII to primed T cells, and antigen-primed antigen-specific B cells are more efficient as APC than naïve B cells. We further conclude that B cells have the potential to play an important role as APC in the development of CIA.


Quantifying stochastic establishment of mutants in microbial adaptation.
Studies of microbial evolution, especially in applied contexts, have focused on the role of selection in shaping predictable, adaptive responses to the environment. However, chance events - the appearance of novel genetic variants and their establishment, i.e. outgrowth from a single cell to a sizeable population - also play critical initiating roles in adaptation. Stochasticity in establishment has received little attention in microbiology, potentially due to lack of awareness as well as practical challenges in quantification. However, methods for high-replicate culturing, mutant labelling and detection, and statistical inference now make it feasible to experimentally quantify the establishment probability of specific adaptive genotypes. I review methods that have emerged over the past decade, including experimental design and mathematical formulas to estimate establishment probability from data. Quantifying establishment in further biological settings and comparing empirical estimates to theoretical predictions represent exciting future directions. More broadly, recognition that adaptive genotypes may be stochastically lost while rare is significant both for interpreting common lab assays and for designing interventions to promote or inhibit microbial evolution.


Arsenic cardiotoxicity: An overview.
Arsenic, a naturally ubiquitous element, is found in foods and environment. Cardiac dysfunction is one of the major causes of morbidity and mortality in the world. Arsenic exposure is associated with various cardiopathologic effects including ischemia, arrhythmia and heart failure. Possible mechanisms of arsenic cardiotoxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels. Several evidences have shown that mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic induced apoptosis. Arsenic trioxide is an effective and potent antitumor agent used in patients with acute promyelocytic leukemia and produces dramatic remissions. As2O3 administration has major limitations such as T wave changes, QT prolongation and sudden death in humans. In this review, we discuss the underlying pathobiology of arsenic cardiotoxicity and provide information about cardiac health effects associated with some medicinal plants in arsenic toxicity.


Long-term results of in situ and extracorporeal surgery for renovascular hypertension caused by fibrodysplasia.
In this study the early and late results of surgical reconstruction for renovascular hypertension caused by fibrodysplasia are evaluated in 53 patients treated between 1962 and 1983. There were 40 female and 13 male patients. The mean blood pressure was 208/126 mm Hg before medical therapy and 171/109 mm Hg thereafter. Bilateral renal artery stenoses were present in 12 patients. In situ revascularization was used in 26 patients and extracorporeal surgery to repair branch artery lesions was performed in 27 patients. Surgical therapy reduced the blood pressure to normal levels with minimal antihypertensive medications. This effect was already apparent 6 to 12 months after operation (mean blood pressure level of 140/90 mm Hg) and it was maintained during a mean follow-up period of 8.4 years (range 1 to 20 years) (mean blood pressure level of 134/85 mm Hg). At 6 to 12 months after operation, 79% of the patients were classified as either cured or improved. At this time the results did not appear to have been influenced by the preoperative duration of hypertension, nor by manifestations of extrarenal arteriosclerosis (ERA) as found in 10 patients, or by the surgical technique applied. But at the end of the long-term follow-up period (mean 8.3 years) the beneficial response rate of 87% appeared to have been adversely influenced by the presence of preoperative ERA, since beneficial response rates were 93% for those without and 67% for those with ERA (p = 0.17). We conclude that renal revascularization is effective both early and late for the treatment of renovascular hypertension caused by fibrodysplasia and that complex renovascular obstruction can be treated effectively with extracorporeal repair.


A biomechanical assessment of disc pressures in the lumbosacral spine in response to external unloading forces.
Axial back pain affects a large percentage of the population. Often aggravated by weight-bearing activity, these patients frequently have associated degenerative or post-traumatic lumbar disc disease. Aquatherapy is frequently used to transition patients from less activity limited by pain to greater activity by reducing weight-bearing load of the lumbar spine. Development of a means to permit patients similar spinal unloading while active during normal daily living would have the potential to promote similar effects. The purpose of this study is to measure internal disc pressure at L4/L5 in response to forces exerted by an external vest. The study hypothesis anticipated an unloading of the lumbar spine during upright posture, as measured by intradicsal pressure at the L4/5 disc, correlating with external forces provided to the trunk by the device. A controlled experimental study of spine biomechanical loading was undertaken using isolated cadaver torsos obtained from an approved tissue source. Ages ranged at death with a mean of 65+/-6 years. The distractive force created by inflating a set of pneumatic lifters within vests for treatment of low back pain were calibrated in a materials testing machine. Effects of inflation on the disc pressures within the lumbar spine then were tested. A microscopic pressure sensor (Samba, Gothenburg, Sweden) was placed into the nucleus of the L4/L5 disc of six isolated cadaver torsos (1 female, 5 male) using a 15-gauge spinal needle under direct fluoroscopic visualization. The pressure sensor was 0.42 mm in diameter, and had a calibrated response range of 0-7500 mm Hg. A pneumatically actuated lumbar vest was fit snugly to the torso. Each torso was supported in an upright, weight-bearing position for testing. The vest was inflated while the internal disc pressure was monitored and recorded. The data were analyzed to test for correlation between the amount of external unloading force provided by the vest and the intradiscal pressure measured in vitro. Application of external loads between the pelvis and ribcage by the vest demonstrated a maximum mean reduction of internal disc pressure at L4/L5 of 25% when the vest was inflated to a level producing approximately 400 N of effective load. The reduction in disc pressure was significantly different compared with baseline (upright, weight-bearing disc pressure without the vest) for all distraction settings (p<.01) except for the very lowest setting which was significant only at p=.025. Spinal unloading with an externally applied vest with adequate surface interface is effective in reducing intradiscal pressures. Ambulatory reduction of pressure would permit beneficial reduction of loads and permit patients with weight-bearing intolerance a better quality of life.


Propofol pretreatment alleviates mast cell degranulation by inhibiting SOC to protect the myocardium from ischemia-reperfusion injury.
Propofol (PPF) has a protective effect on myocardial ischemia-reperfusion (I/R) injury (MIRI). The purpose of this study was to investigate whether the myocardial protective effect of propofol is related to the inhibition of mast cell degranulation and explore the possible mechanisms involved. Our in vivo results showed that compared with the sham group, cardiac function, infarct size, histopathological damage, apoptosis, and markers of myocardial necrosis were significantly increased in the ischemia-reperfusion group, and propofol pretreatment alleviated these effects. In the coculture system, propofol-treated mast cells reduced their tryptase activity, resulting in cardiomyocyte protective effects, such as decreased apoptosis of cardiomyocytes and decreased expression of myocardial necrosis markers. Finally, experimental results in vitro revealed that thapsigargin (TG) can increase mast cell degranulation, tryptase release, calcium ion concentration, and the expression of STIM1 and Orai1 induced by H/R, but propofol pretreatment can partially reverse the above effects. These results suggested that the cardioprotective effect of propofol is achieved in part by inhibiting calcium influx through store-operated Ca2+ channels (SOCs) and thus alleviating mast cell degranulation.


Active fractions of golden-flowered tea (Camellia nitidissima Chi) inhibit epidermal growth factor receptor mutated non-small cell lung cancer via multiple pathways and targets in vitro and in vivo.
As a medicine-food homology (MFH) plant, golden-flowered tea (Camellia nitidissima Chi, CNC) has many different pharmacologic activities and is known as "the queen of the tea family" and "the Panda of the Plant world". Several studies have revealed the pharmacologic effects of CNC crude extract, including anti-tumor, anti-oxidative and hepatoprotective activity. However, there are few studies on the anti-tumor active fractions and components of CNC, yet the underlying mechanism has not been investigated. Thus, we sought to verify the anti-non-small cell lung cancer (NSCLC) effects of four active fractions of CNC. Firstly, we determined the pharmacodynamic material basis of the four active fractions of CNC (Camellia. leave. saponins, Camellia. leave. polyphenols, Camellia. flower. saponins, Camellia. flower. polyphenols) by UPLC-Q-TOF-MS/MS and confirmed the differences in their specific compound contents. Then, MTT, colony formation assay and EdU incorporation assay confirmed that all fractions of CNC exhibit significant inhibitory on NSCLC, especially the Camellia. leave. saponins (CLS) fraction on EGFR mutated NSCLC cell lines. Moreover, transcriptome analysis revealed that the inhibition of NSCLC cell growth by CLS may be via three pathways, including "Cytokine-cytokine receptor interaction," "PI3K-Akt signaling pathway" and "MAPK signaling pathway." Subsequently, quantitative real-time PCR (RT-qPCR) and Western blot (WB) revealed TGFB2, INHBB, PIK3R3, ITGB8, TrkB and CACNA1D as the critical targets for the anti-tumor effects of CLS in vitro. Finally, the xenograft models confirmed that CLS treatment effectively suppressed tumor growth, and the key targets were also verified in vivo. These observations suggest that golden-flowered tea could be developed as a functional tea drink with anti-cancer ability, providing an essential molecular mechanism foundation for MFH medicine treating NSCLC.


Oestrogen and glucocorticoid responsive elements are closely related but distinct.
DNA sequences recognized by the glucocorticoid receptor are termed glucocorticoid-responsive elements because of their stimulatory effect on transcription. An oligonucleotide of 15 base pairs having partial or perfect symmetry is necessary for glucocorticoid induction and this same oligonucleotide is surprisingly also recognized by the progesterone receptor. Here we define a palindromic sequence of 15 base pairs, modelled after a sequence element shared by the vitellogenin genes of frog and chicken, which confers oestrogen inducibility on a heterologous promoter and can be converted into a glucocorticoid-responsive element by substitution of one or two bases at homologous positions in the palindrome. Considered with the observation that the DNA-binding domains of steroid receptors are closely related, this finding demonstrates that the steroid-responsive elements constitute a family of related DNA sequences.


Effects of Killari earthquake on the paleo-channel of Tirna River Basin from Central India using anisotropy of magnetic susceptibility.
The Killari Earthquake (Moment magnitude 6.1) of September 30, 1993, occurred in the state of Maharashtra, India, has an epicenter (18°03' N, 76°33' E) located at ~ 40 km SSW of Killari Town. The ~ 125 km long basin of Tirna River, close to the Killari Town, currently occupies the area that has witnessed episodic intra-cratonic earthquakes, including the Killari Earthquake, during last 800 years. The anisotropy of magnetic susceptibility (AMS) study was performed on ~ 233 soft sedimentary core samples from six successions located in the upper to lower stream of the Tirna River basin in the present study in order to evaluate the effects of earthquake on the river flow dynamics and its future consequence. The AMS Kmax orientations of the samples from the upper reach of the river section suggest that the sedimentation in this part of the river was controlled by a N-S to NNW-SSE fluvial regime with a low or medium flow velocity. In the middle reaches of the basin, an abrupt shift in the palaeo-flow direction occurred to W-E with low velocity flow. However, a NW-SE higher palaeo-flow regime is identified in the following central part of the basin in down-stream direction, followed by a low-velocity palaeo-flow regime at the lower reach of the Tirna basin. We attribute the sudden high flow velocity regime in the central part of the river basin to an enhanced gradient of the river that resulted from the reactivation of a NW-SE fault transecting the Tirna River basin at the Killari Town. As the NW-SE faulting in regional scale is attributed as the main cause of Killari Earthquake, the reactivation of this fault, thus, could enhance the further possibility of an earthquake in near future, and hence leading to devastating flood in the almost flat-lying downstream part of the Tirna River.


Prostate health index (PHI) as a reliable biomarker for prostate cancer: a systematic review and meta-analysis.
Prostate cancer (PCa) represents the second most common solid cancer in men worldwide. In the last decades, the prostate health index (PHI) emerged as a reliable biomarker for detecting PCa and differentiating between non-aggressive and aggressive forms. However, before introducing it in clinical practice, more evidence is required. Thus, we performed a systematic review and meta-analysis for assessing the diagnostic performance of PHI for PCa and for detecting clinically significant PCa (csPCa). Relevant publications were identified by a systematic literature search on PubMed and Web of Science from inception to January 11, 2022. Sixty studies, including 14,255 individuals, met the inclusion criteria for our meta-analysis. The pooled sensitivity and specificity of PHI for PCa detection was 0.791 (95%CI 0.739-0.834) and 0.625 (95%CI 0.560-0.686), respectively. The pooled sensitivity and specificity of PHI for csPCa detection was 0.874 (95%CI 0.803-0.923) and 0.569 (95%CI 0.458-0.674), respectively. Additionally, the diagnostic odds ratio was 6.302 and 9.206, respectively, for PCa and csPCa detection, suggesting moderate to good effectiveness of PHI as a diagnostic test. PHI has a high accuracy for detecting PCa and discriminating between aggressive and non-aggressive PCa. Thus, it could be useful as a biomarker in predicting patients harbouring more aggressive cancer and guiding biopsy decisions.


Low frequency electric and magnetic fields have different effects on the cell surface.
There is a considerable controversy over the nature of weak electromagnetic-field effects in living organisms. Part of the controversy can be traced to a lack of understanding of whether electric or magnetic fields are involved in producing bioeffects. We find that both 60 Hz electric and magnetic fields alter the cell surface of Physarum polycephalum. Exposure to electric fields increases the negative charge on the cell surface while magnetic-field exposure decreases the hydrophobic character of the surface. These effects appear to be additive and independent of the waveform of the applied fields.


Hepatitis A outbreak in Barcelona among men who have sex with men (MSM), January-June 2017: A hospital perspective.
Acute hepatitis A is transmitted mainly via the faecal-oral route and/or contaminated aliment. Furthermore, several outbreaks in the men who have sex with men (MSM) population classified hepatitis A as a sexually transmitted disease (STD). We aimed to clarify an ongoing hepatitis A outbreak in Barcelona with respect to patients' characteristics and viral phylogenetic analysis. We prospectively analyzed 46 cases of hepatitis A infection that were registered in our hospital between January and June 2017. We evaluated demographics data, risk factors, presenting symptoms, sexual orientation, comorbidities and further STD infections. The phylogenetic correlation of the current circulating viruses among them and other hepatitis A strains was assessed by sequencing of the VP1/P2A region. Most patients were male (44, 96%) with median age 33.5 years (range 28-50). Thirty-one (67%) were MSM and 18 (39%) required hospitalization. Molecular phylogenetic analyses revealed that all patients were infected by hepatitis A subgenotype IA strains. Moreover, current strains comprised 3 distinct clusters, previously reported in ongoing outbreaks in the United Kingdom, Berlin and the Netherlands. However, these strains were phylogenetically diverse to those previously reported in Barcelona metropolitan region. Ongoing hepatitis A outbreak in Barcelona affects primarily the MSM community and is phylogenetically linked to current hepatitis A outbreaks described in other European countries. As a result of the high admission rate, these outbreaks may impact the admission pattern of referral liver units. Control measures, for example vaccinations programs tailored to the MSM community, must be taken to control further spreading.


The antioxidant activities of garlic polysaccharide and its derivatives.
Garlic was used as raw material to extract garlic polysaccharide (P) with hot water extraction method. IR and NMR spectra showed that the preparation of sulfated garlic polysaccharide (SP), phosphorylated garlic polysaccharide (PP) and carboxymethylated garlic polysaccharide (CMP) was successful. The sugar content of P, SP, PP and CMP was determined, and their degree of substitution was measured. Hydroxyl radical scavenging ability, superoxide anion scavenging ability, significant reduction capacity, and anti-lipid peroxidation ability of P, SP, PP, CMP and VC were determined. It showed that the introduction of substituents had different effects on the antioxidant activities of P.


Increasing specificity in high-throughput yeast two-hybrid experiments.
Since its inception, the yeast two-hybrid (Y2H) system has proven to be an efficient system to identify novel protein-protein interactions. However, Y2H screens are sometimes criticized for generating high rates of false-positives. Minimizing false-positive interactions is especially important in proteome wide high-throughput (HT) Y2H. Here, we summarize various approaches that reduce false-positives in HT-Y2H projects. We evaluated the potential of examining putative positives after removing the prey encoding plasmid by negative selection. We found that this method reliably identifies false-positives caused by spontaneous conversion of baits into auto-activators and provides significant time-savings in HT screens. In addition, we present a method to eliminate an important source of false-positives: contaminating prey plasmids. Y2H interactors can be wrongly identified due to the presence of two or more different plasmids in the cells of a single yeast colony. Of these independent plasmids, only one encodes a genuine interactor. Contaminating plasmids are eliminated by extended culture of yeast cells under positive selection for the interaction, allowing the identification of the true interaction partner.


Cancer proteomics by quantitative shotgun proteomics.
A major scientific challenge at the present time for cancer research is the determination of the underlying biological basis for cancer development. It is further complicated by the heterogeneity of cancer's origin. Understanding the molecular basis of cancer requires studying the dynamic and spatial interactions among proteins in cells, signaling events among cancer cells, and interactions between the cancer cells and the tumor microenvironment. Recently, it has been proposed that large-scale protein expression analysis of cancer cell proteomes promises to be valuable for investigating mechanisms of cancer transformation. Advances in mass spectrometry technologies and bioinformatics tools provide a tremendous opportunity to qualitatively and quantitatively interrogate dynamic protein-protein interactions and differential regulation of cellular signaling pathways associated with tumor development. In this review, progress in shotgun proteomics technologies for examining the molecular basis of cancer development will be presented and discussed.


Keratinization and lipogenesis in epidermal derivatives of the zebrafinch, Taeniopygia guttata castanotis (Aves, Passeriformes, Ploecidae) during embryonic development.
Little is known of the lipid content of beta-keratin-producing cells such as those of feathers, scutate scales, and beak. The sequence of epidermal layers in some apteria and in interfollicular epidermis in the zebrafinch embryo (Taeniopygia guttata castanotis) was studied. Also, the production of beta-keratin in natal down feathers and beak was ultrastructurally analyzed in embryos from 3-4 to 17-18 days postdeposition, before hatching. Two layers of periderm initially cover the embryo, but there are eventually 6-8 over the epidermis of the beak. In the beak and sheath cells of feathers, peridermal granules are numerous at 12-14 days postdeposition but they are less frequent in apteria. These granules swell and disappear during sheath or peridermal degeneration at 15-17 days postdeposition. A thin beta-keratin layer forms under the periderm among feather germs of pterylous areas but is discontinuous or disappears in apteria. In differentiating cells of barbs, barbules, and calamus cells of natal down, electron-dense beta-keratin filaments form bundles oriented along the main axis of these cells. Cells of the pulp epidermis and collar, at the base of the follicle, contain lipids and bundles of alpha-keratin filaments. Degenerating pulp cells show vacuolization and nuclear pycnosis. During beta-keratin packing, keratin bundles turn electron-pale, perhaps due to the addition of lipids to produce the final, homogenous beta-keratin matrix. In contrast to the situation in feathers, in the cells of beak beta-keratin packets are irregularly oriented. In both feather and beak epidermal cells the Golgi apparatus and smooth endoplasmic reticulum produce vesicles containing lipid-like material which is also found among forming beta-keratin. The contribution of lipids or lipoprotein to the initial aggregation of beta-keratin molecules is discussed.


Spatial heterogeneity and microvascular fluid exchange: a simple macroscopic equation.
The effect of the spatial distribution of capillary membrane "pores" on the estimate for the hydraulic conductivity (Lp) and the reflection coefficient (sigma s) in the presence of an axial gradient in the hydrostatic pressure difference (delta P) is examined. The differential fluid balance is integrated along the length of the capillary and a simple analytic solution is obtained for a capillary membrane of arbitrary structure. The effective hydrostatic pressure difference, (delta P)eff, is not simply the average of the arterial [(delta P)a] and venous [(delta P)v] pressure differences but is instead found to be (delta P)eff identical to [(delta P)a + (delta P)v]/2 + kappa [(delta P)a - (delta P)v]/2, where kappa identical to 1 - 2 (Lp1/Lp). The two macroscopic coefficients, Lp and Lp1, are related to integrals of the pore density along the length of the capillary. Failure to account for spatial heterogeneity may lead to an incorrect interpretation of the experimental data, e.g., the estimate for sigma s could be greater than 1 or less than 0 depending on the pore distribution and pressure gradient along the capillary. The single capillary hydraulic conductivity measurements of Gore [1982), Amer. J. Physiol. 242, H268-H287) and data on the microvascular pressure distributions (Bohlen and Gore (1977), Microvasc. Res. 14, 251-264) are used to estimate the magnitude of these effects.


Molecular survey of bovine vector-borne pathogens in Cebu, Philippines.
Vector-borne diseases (VBDs) continue to threaten the worldwide livestock industry, but comprehensive epidemiological surveys on such diseases have not been conducted in the Philippines. In the present study, we screened 408 bovine blood samples from 9 areas in Cebu, Philippines, for various VBD pathogens using specific PCR assays. The results revealed prevalences of 54.7, 15.4, 10.0, and 12.0% for Anaplasma spp., Babesia bigemina, Babesia bovis, and Trypanosoma (Tr.) theileri, respectively. In contrast, none of the samples were positive for Trypanosoma (Tr.) evansi, Theileria (Th.) orientalis, and Theileria (Th.) annulata. Mixed infections were observed in 24.2% of the samples tested. Phylogenetic analysis based on the 16S rRNA gene revealed that the Anaplasma spp. sequences from the present study were genetically close either to Anaplasma marginale or Anaplasma phagocytophilum. In addition, B. bovis RAP-1 and Babesia bigemina AMA-1 gene sequences were identical and monophyletic to other known B. bovis and B. bigemina sequences. On the other hand, Tr. theileri cathepsin-L like protein gene sequences shared 97.1-100% identities with those from the USA and Brazil and clustered within a single genotype in the phylogenetic tree. The molecular identification of several VBD pathogens in Cebu cattle calls for the implementation of control measures to prevent the spread of these pathogens to nearby localities or islands, and ultimately, economic losses to the Philippine economy.


Cytochrome c2 and reaction center of Rhodospeudomonas spheroides Ga. membranes. Extinction coefficients, content, half-reduction potentials, kinetics and electric field alterations.
The reduced minus oxidized extinction coefficients (delta epsilon-red-ox) of reaction center P605 when in the chromatophore is about 20% smaller than in the detergent-isolated state. Presumably the coupling of the reaction center protein to the antenna bacteriochlorophylls and carotenoids causes this hypochromism. The chromatophore values for P605 are 19.5 mM- minus 1 times cm- minus 1 with the spectrophotometer on single beam mode at 605 nm, and 29.8 mM- minus 1 times cm- minus 1 on dual wavelength mode set at 605--540 nm. Cytochrome c2, which is not affected by detergent, has a delta epsilon-red-ox value at 550--540 nm of 19.0 mM- minus 1 times cm- minus 1.2. The total bacteriochlorophyll to reaction center bacteriochlorophyll protein (P) ratio is about 100: 1. The cytochrome c2: reaction center protein ratio approaches 2. In current French press chromatophore preparations, about 70% of the reaction centers are each associated on a rapid kinetic basis with two cytochrome c2 molecules (intact P-c2 units). The remaining reaction center proteins are not associated with cytochrome c2 on a kinetically viable bais and may be the result of damage incurred during mechanical rupture of the cells. 3...


Prognostic significance of plasma visfatin levels in patients with ischemic stroke.
Plasma visfatin concentration has been enhanced in ischemic stroke. The aim of the current investigation was to test whether determination of visfatin in plasma is associated with 6-month clinical outcomes including mortality and unfavorable outcome (modified Rankin Scale score>2) in the patients with ischemic stroke. Between July 2009 and January 2012, plasma visfatin concentrations of 186 patients and 100 healthy individuals were quantified by enzyme-linked immunosorbent assay. Plasma visfatin concentrations were higher in patients than in healthy individuals (108.5±41.1 ng/mL vs. 13.8±3.9 ng/mL, P<0.001). A logistic regression analysis selected plasma visfatin concentration as an independent predictor for 6-month clinical outcomes (both P<0.01). Using receiver operating characteristic curve analysis, plasma visfatin concentration was found to predict 6-month clinical outcomes with the high predictive performance. The predictive value of visfatin was in the range of National Institutes of Health Stroke Scale score (both P>0.05). Combined use of visfatin and National Institutes of Health Stroke Scale score did not improve the predictive significance (both P>0.05). Thus, visfatin may help in the prediction of long-term clinical outcomes in patients with ischemic stroke.


N-Butyl Cyanoacrylate Glue Versus Nonspherical Polyvinyl Alcohol Particles For Prostatic Arterial Embolization To Treat Benign Prostatic Hyperplasia: Safety and Efficacy.
Our aim is to compare N-butyl cyanoacrylate (NBCA) glue and non-spherical polyvinyl alcohol (PVA) particles for prostatic artery embolization (PAE) for patients with benign prostatic hyperplasia (BPH) to treat lower urinary tract symptoms (LUTS) and report their feasibility, safety, and short-term effectiveness. 110 patients (mean age: 72.6 years) with BPH related to LUTS were divided into two groups, PAE was performed in one group with 250 - 355 μm non-spherical PVA particles. Whereas, the other group received a mixture of NBCA glue/ lipiodol for PAE. PAE was technically successful in all 110 patients (100 %). During 6 months follow up, we found that in patients who received NBCA glue, the mean of prostatic volume (PV) was significantly reduced compared to baseline (67.1 ± 8.5 to 40.2 ± 5.4), International Prostate Symptom Score (IPSS) (25.7 ± 4.3 to 7.2 ± 1.09), Quality of life (QoL) (4.43 ± 0.27 to 1.58 ± 2.27); whereas, the mean of Peak urinary flow (Qmax) increased significantly from baseline to 6 months (8.6 ± 2.3 to 15.4 ± 2.3), International Index of Erectile Function (IIEFS) (9.46 ± 1.51 to 19.3 ± 1.33). Meanwhile, non-spherical PVA particles used in the other group show that PV significantly reduced from baseline to 6 months (68.2 ± 8.32 to 38.8 ± 6.13), IPSS (25.0 ± 3.59 to7.24 ± 0.83), QoL (4.43 ± 0.24 to1.56 ± 0.55). The mean for Qmax increased from baseline to 6 months (7.19 ± 1.67 to15.1 ± 2.42), IIEFS (9.22 ± 1.30 to 19.5 ± 0.96). PAE with NBCA glue and non-spherical PVA particles is feasible, safe, and effective for patients with BPH related-LUTS. This gives the physicians options to choose between embolizing agents based on the architecture of the prostatic artery.


Growing up fast: manipulating the generation time of trees.
Domestication and genetic improvement of trees is far behind that of herbaceous plants owing to their long generation times, which result from the existence of a long juvenile phase of reproductive incompetence. During recent years, significant progress has been made towards understanding the molecular basis of flowering transition in model herbaceous species. Some of the genes identified have been shown to efficiently accelerate reproductive development when ectopically expressed in transgenic plants, including trees. These results provide new clues as to the molecular basis of reproductive competence in trees and suggest ways to accelerate their genetic improvement.


Effects of trace elements contaminations on the larval development of Paracentrotus lividus using an innovative experimental approach.
Several experiments were performed using larvae of Paracentrotus lividus (Lamarck, 1816) in order to determine the consequences of different chronic contamination with mixtures of (i) fifteen trace elements from concentrations measured in the world ocean seawater, and (ii) seven trace elements from contamination resulting from mining. To predict the impact of increased marine pollution, higher concentrations were also used. These bioassays were conducted using spawners collected from Calvi (reference site, Corsica), and Albo (mining area, Corsica). The effects of trace elements have been studied on the entire larval development. The results show wider arms and delayed development as the number and concentration of trace elements increases. Therefore, the synergy between the different trace elements is of paramount importance with regard to the impact on organisms. Probably due to a hormesis phenomenon, larvae contaminated with seven trace elements at average concentrations developed more quickly. This work also highlighted the importance of the origin of spawners in ecotoxicological studies. To our knowledge, this is the first study to investigate the effects of such a broad combination of trace elements for chronic contamination on the entire larval stage of Paracentrotus lividus.


Characterisation of xenopsin immunoreactivity derived from pepsinised human skin and possible mechanism of in vivo generation.
Human skin was subjected to a variety of extraction and enzymatic digestion procedures. Extracts and digests were subjected to neurotensin and xenopsin radioimmunoassays of known specificity. No neurotensin immunoreactivity was detected in any preparation with any region-specific antiserum. C-terminal xenopsin immunoreactivity was present in skin homogenates following incubation with both soluble and solid-phase pepsin and in those incubated with a leucocyte lysate or purified cathepsin D. The generation of xenopsin immunoreactivity was dependent on low pH and enzymes of pepsin-type specificity acting on a tissue precursor of approximately 30 kDa. Gel permeation chromatography of skin-derived xenopsin immunoreactivity identified a single molecular species larger than synthetic xenopsin which was resolved into two components by reverse-phase HPLC with retention times similar to synthetic xenopsin and kinetensin. Human skin thus contains a high-molecular-weight precursor protein and an endogenous acid protease, cathepsin D, capable of generating a peptide of similar size and C-terminal structure to amphibian xenopsin under acidic conditions such as might occur locally in wounds or at sites of inflammation.


Endocrine, cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats.
Post traumatic stress disorder (PTSD) is characterised by hyperarousal, anxiety and amnesic symptoms. Deficits in explicit memory recall have been causally related to volume reductions of the hippocampus and prefrontal cortex. While stress-related glucocorticoid secretion appears involved in this apparent atrophy, there is also evidence for low plasma cortisol in PTSD. Prior exposure to trauma is an important risk factor for PTSD, suggesting a role for sensitisation. Using Sprague-Dawley rats, we studied the effects of a time-dependent sensitisation (TDS) model of stress on spatial memory deficits, 1 week post-stress, using the Morris water maze. Basal and 7-day post-stress plasma corticosterone levels were also determined. Due to the putative role of serotonin in anxiety and stress, and in the treatment of PTSD, hippocampal 5HT(1A) and prefrontal cortex 5HT(2A) radioligand binding studies were performed. TDS stress evoked a marked deficit in spatial memory on day 7 post TDS stress, coupled with significantly depressed plasma corticosterone levels. Cognitive and endocrine changes at day 7 post stress were associated with a significant increase in receptor density (B(max)) and a significant decrease in receptor affinity (K(d)) for hippocampal 5HT(1A) receptors. The B(max) of prefrontal cortex 5HT(2A) receptors were unaffected, but K(d) was significantly increased. We conclude that TDS stress evokes cognitive and endocrine changes characteristic of PTSD. Moreover, TDS stress induces diverse adaptive 5HT receptor changes in critical brain areas involved in emotion and memory that may underlie the effect of stress on cognitive function.


Brachytherapy with surgical resection as salvage treatment for recurrent high-grade meningiomas: a matched cohort study.
To evaluate surgical resection with brachytherapy placement as a salvage treatment in patients with recurrent high-grade meningioma who exhausted prior external beam treatment options. Single-center retrospective review of our institutional experience of brachytherapy implantation from 2012 to 2018. The primary outcome of the study was progression free survival (PFS). Secondary outcomes included overall survival (OS) and complications. A matched cohort of patients not treated with brachytherapy over the same time period was evaluated as a control group. All patients had received prior radiation treatment and underwent planned gross total resection (GTR) surgery. A total of 27 cases were evaluated. Compared with prior treatment, brachytherapy implantation demonstrated a statistically significant improvement in tumor control [HR 0.316 (0.101 - 0.991), p = 0.034]. PFS-6 and PFS-12 were 92.3% and 84.6%, respectively. Compared with the matched control cohort, brachytherapy treatment demonstrated improved PFS [HR 0.310 (0.103 - 0.933), p = 0.030]. Overall survival was not statistically significantly different between groups [HR 0.381 (0.073 - 1.982), p = 0.227]. Overall postoperative complications were comparable between groups, although there was a higher incidence of radiation necrosis in the brachytherapy cohort. Brachytherapy with planned GTR improved PFS in recurrent high-grade meningioma patients who exhausted prior external beam radiation treatment options. Future improvement of brachytherapy dose delivery methods and techniques may continue to prolong control rates and improve outcomes for this challenging group of patients.


AIBP, Angiogenesis, Hematopoiesis, and Atherogenesis.
The goal of this manuscript is to summarize the current understanding of the secreted APOA1 binding protein (AIBP), encoded by NAXE, in angiogenesis, hematopoiesis, and inflammation. The studies on AIBP illustrate a critical connection between lipid metabolism and the aforementioned endothelial and immune cell biology. AIBP dictates both developmental processes such as angiogenesis and hematopoiesis, and pathological events such as inflammation, tumorigenesis, and atherosclerosis. Although cholesterol efflux dictates AIBP-mediated lipid raft disruption in many of the cell types, recent studies document cholesterol efflux-independent mechanism involving Cdc42-mediated cytoskeleton remodeling in macrophages. AIBP disrupts lipid rafts and impairs raft-associated VEGFR2 but facilitates non-raft-associated NOTCH1 signaling. Furthermore, AIBP can induce cholesterol biosynthesis gene SREBP2 activation, which in turn transactivates NOTCH1 and supports specification of hematopoietic stem and progenitor cells (HSPCs). In addition, AIBP also binds TLR4 and represses TLR4-mediated inflammation. In this review, we summarize the latest research on AIBP, focusing on its role in cholesterol metabolism and the attendant effects on lipid raft-regulated VEGFR2 and non-raft-associated NOTCH1 activation in angiogenesis, SREBP2-upregulated NOTCH1 signaling in hematopoiesis, and TLR4 signaling in inflammation and atherogenesis. We will discuss its potential therapeutic applications in angiogenesis and inflammation due to selective targeting of activated cells.


Changes in biochemical properties and pectin nanostructures of juice sacs during the granulation process of pomelo fruit (Citrus grandis).
Postharvest granulation is a severe physiological disorder in citrus fruit that may be related to pectin metabolism. This study was designed to analyze the changes in fruit quality and pectin metabolism of pomelo fruit during granulation from expansion, gelation to lignification. Fruit quality showed a decrease starting from the gelation stage. Contents of water-soluble pectin, chelate-soluble pectin, sodium carbonate-soluble pectin and calcium, and activity of pectin methylesterase increased, while polygalacturonase activity decreased upon granulation. Atomic force microscopy analysis showed that both length and width of those three types of pectin molecules increased during granulation, accompanied by the decrease of linear structure molecules of pectin and the increase of pectin polymers, and multi-branched pectin tending to form cross-linked structure. Complex network of pectin might be remodeled during granulation process that immobilized the free water in juice sacs and induced the gelation occurrence, further promoted the granulation process.


Role of prostaglandin, endothelin and sympathetic nervous system on the L-NAME-induced pressor responses in spontaneously hypertensive rats.
We tested the hypothesis that in spontaneously hypertensive rat (SHR) NO produced centrally influences the resting arterial blood pressure by attenuating mechanisms involving prostaglandins, angiotensin II, endothelin and sympathetic nervous system. L-NAME (200 micro g/5 micro l), an inhibitor of NO synthase, administered intracerebroventricularly (i.c.v.) to awake and freely moving rats increased mean arterial blood pressure (MABP) in a biphasic pattern: an early transient increase within 1 min and a late prolonged response starting at 45 min and persisting for the duration of experiment (180 min). The two pressor responses involve different neurochemical mechanisms and, based on their latencies, they appear to reflect different anatomical sites of action of L-NAME. The late, but not the early pressor response, was prevented by pretreatment with chlorisondamine (2.5 mg/kg, i.v.), a ganglionic blocker, indicating its dependence on the sympathetic nervous system. Both pressor responses were abolished by i.c.v. pretreatment with indomethacin (200 micro g/5 micro l, i.c.v.), an inhibitor of cyclo-oxygenase, showing that they are mediated by prostaglandin(s). In contrast, losartan (25 micro g/5 micro l), an angiotensin II AT(1) receptor antagonist, had no effect. The initial pressor response was also attenuated by pretreatment with the endothelin ET(A)/ET(B) receptor antagonist, PD 145065 (48 micro g/2 micro l, i.c.v.). Intravenous pretreatment with another ET(A)/ET(B) receptor antagonist, L-754,142 (15 mg/kg as a bolus+15 mg/kg/h for 180 min), however, attenuated both responses to L-NAME. It is possible that L-754,142 crossed the blood-brain barrier and blocked, in addition, central ET(A)/ET(B) receptors. These studies show that NO synthesized in the brain attenuates pressor mechanisms involving prostaglandin, endothelin and sympathetic nervous system, but not angiotensin II, to modulate resting arterial blood pressure.


Self-association of adenosine 5'-monophosphate (5'-AMP) as a function of pH and in comparison with adenosine, 2'-AMP and 3'-AMP.
The concentration dependence of the chemical shifts for protons H-2, H-8, and H-1' of adenosine (Ado), 2'-AMP, 3'-AMP and 5'-AMP was measured in D2O at 27 degrees C under several degrees of protonation. All results are consistent with the isodesmic model of indefinite noncooperative stacking. The association constants for Ado decrease with increasing protonation: Ado (K = 15 M-1) greater than D(Ado)+/Ado (6.0 M-1) greater than D(Ado)+ (0.9 M-1). In contrast, a maximum is observed with 5'-AMP: 5'-AMP2- (K = 2.1 M-1) less than D(5'-AMP)- (3.4 M-1) less than D2(5'-AMP) +/- /D(5'-AMP)- (5.6 M-1) greater than D2(5'-AMP) +/- (approximately 2 M-1) greater than D3(5'-AMP)+ (less than or equal to 1 M-1). Self-stacking is most pronounced here if 50% of the adenine residues are protonated at N-1; complete base protonation reduces the stacking tendency drastically. Comparing the self-association of 2'-, 3'- and 5'-AMP shows that there is no influence of the phosphate-group position in the 2-fold negatively charged species, i.e., K congruent to 2 M-1 for all three AMP2- species. More importantly, there is also no significant influence observed if the stacking tendency of the three D2(AMP) +/- /D(AMP)-1:1 mixtures is compared (K congruent to 6-7 M-1); moreover, the measured association constants are within experimental error identical with the constant determined for D(Ado)+/Ado (K = 6.0 M-1). This indicates that any coulombic contribution between the -PO3(H)- group and the H+ (N-1) unit of the adenine residue to the stability of the mentioned stacks in D2O is small. However, experiments in 50% (v/v) dioxane-D8/D2O with the D2(5'-AMP) +/- /D(5'-AMP)- 1:1 system reveal, despite its low solubility, that coulombic interactions contribute to the self-association in an environment with a reduced polarity (compared to that of water). The implications of these observations for biological systems are briefly indicated.


Protocol guided bleeding management improves cardiac surgery patient outcomes.
Excessive bleeding is a risk associated with cardiac surgery. Treatment invariably requires transfusion of blood products; however, the transfusion itself may contribute to postoperative sequelae. Our objective was to analyse a quality initiative designed to provide an evidenced-based approach to bleeding management. A retrospective analysis compared blood product transfusion and patient outcomes 15 months before and after implementation of a bleeding management protocol. The protocol incorporated point-of-care coagulation testing (POCCT) with ROTEM and Multiplate to diagnose the cause of bleeding and monitor treatment. Use of the protocol led to decreases in the incidence of transfusion of PRBCs (47·3% vs. 32·4%; P < 0·0001), FFP (26·9% vs. 7·3%; P < 0·0001) and platelets (36·1% vs. 13·5%; P < 0·0001). During the intra-operative period, the percentage of patients receiving cryoprecipitate increased (2·7% vs. 5·1%; P = 0·002), as did the number of units transfused (248 vs. 692; P < 0·0001). The proportion of patients who received tranexamic acid increased (13·7% to 68·2%; P < 0·0001). There were reductions in re-exploration for bleeding (5·6% vs. 3·4; P = 0·01), superficial chest wound (3·3% vs. 1·4%; P = 0·002), leg wound infection (4·6% vs. 2·0%; P < 0·0001) and a 12% reduction in mean length of stay from operation to discharge (95%: 9-16%, P < 0·0001). Acquisition cost of blood products decreased by $1 029 118 in the 15-month period with the protocol. The implementation of a bleeding management protocol supported by POCCT in a cardiac surgery programme was associated with significant reductions in the transfusion of allogeneic blood products, improved outcomes and reduced cost.


Solubilization of membrane-bound adenylate cyclase of isolated rat adrenal cortex cells.
The membrane-bound adenylase cyclase (ATP pyrosphosphate-lyase (cyclizing), EC 126.96.36.199) of isolated rat adrenal cortex cells can be rendered soluble using 0.02 M Lubrol 12A9. The solubilized enzyme can be filtered through Milipore filters with pores 0.22 micron in diameter. Using gel filtration, on Sephadex G-200, adenylate cyclase activity was eluted with a distribution coefficient of 0.139, whereas on Sephadex G-100 the activity was eluted in the excluded volume. Half-maximum activation of the postulated guanyl nucleotide regulator site of adenylate was achieved with 5'-guanylyl-imidodiphosphate at a concentration of 1 . 10(-6)M. In contrast, however, using intact isolated rat adrenal cortex cells the guanyl nucleotide regulator site could not be stimulated by 5'-guanylyl-imidodiphosphate.


Stimulation of tumor necrosis factor-induced human myelogenous leukemic cell differentiation by high molecular weight PSK subfraction.
The mouse macrophage-like cell line, J774.1, spontaneously released differentiation-inducing factor(s). When these cells were treated with a protein-bound polysaccharide, PSK, significantly higher amounts of differentiation-inducing activity were accumulated in the culture supernatant. PSK directly stimulated human myelogenous leukemic cell differentiation induced by J774.1 conditioned medium or by tumor necrosis factor. Among four subfractions of PSK, only the highest molecular weight fraction (MW greater than 200 kD) exerted such a stimulating effect.


Gender Stereotypes and Discrimination: How Sexism Impacts Development.
In this chapter, we summarize and integrate some of the latest developmental science research on gender stereotypes and discrimination in childhood and adolescence. We focus on five forms of sexism: (a) stereotypes and discrimination against boys regarding their school behaviors and disciplinary actions; (b) stereotypes and discrimination against girls in science, technology, engineering, and mathematics (STEM) domains; (c) stereotypes and discrimination in sports; (d) peer gendered harassment, including sexual harassment and teasing because of gender atypicality or nonconformity; and (e) sexualized gender stereotypes that sexually objectify girls and assume boys are sexually voracious. First, we document each type of sexism and examine children's awareness and perceptions of that bias, including their own self-reports and attributions. We examine the implications of this sexism for children and adolescents' developmental health (i.e., social, academic, and psychological well-being). We then draw connections between these various areas of research, focusing on how these different forms of sexism interact to reduce equity and justice among children and negatively impact positive developmental outcomes. The chapter concludes with suggestions for future research.


Role of alphaBI5 and alphaBT162 residues in subunit interaction during oligomerization of alphaB-crystallin.
To determine whether the residues in the NH(2)- and COOH-terminal extensions interact with one another during oligomerization of alphaB-crystallin. Site-directed mutagenesis was used to mutate alphaBI5 and alphaBT162 residues to Cys. The recombinant I5C and T162C proteins were expressed in Escherichia coli cells and purified using chromatographic techniques. These proteins were analyzed by SDS-PAGE and mass spectrometry and characterized by multi-angle light scattering and circular dichroism (CD) spectroscopy methods. Fluorescence resonance energy transfer (FRET) assay was used to determine the interaction between the subunits. Dimer formation was observed in both alphaBI5C and alphaBT162C in storage at 4 degrees C. During air oxidation at room temperature, alphaBT162C formed dimers to a greater extent than alphaBI5C. The average molar masses, secondary structures, and chaperone-like activities of the reduced forms of I5C and T162C were comparable to that of wild type alphaB-crystallin. The oligomeric assembly of reduced forms of I5C and T162C appeared homogenous under JEOL 1200EX Electron microscope whereas the oxidized proteins appeared as irregular aggregates. FRET assay demonstrated interactions between alphaBI5C-alphaBI5C and alphaBT162C-alphaBT162C. However, there was no evidence of an interaction between alphaBI5C and alphaBT162C residues during oligomerization. This study suggests that residues from the NH(2)- and COOH-terminal regions in alphaB-crystallin interact with residues from the corresponding regions of another subunit, but there exists no interaction between the residues at the COOH-terminal extension region and the residues at the NH(2)-terminal region.


Pentoxifylline inhibits the fibrogenic activity of pleural effusions and transforming growth factor-beta.
Physiopathology of organ fibrosis is far from being completely understood, and the efficacy of the available therapeutic strategies is disappointing. We chose pleural disease for further studies and addressed the questions of which cytokines are relevant in pleural fibrosis and which drugs might interrupt its development. We screened pleural effusions for mediators thought to interfere with fibrogenesis (transforming growth factor-beta (TGF-beta), tumour necrosis factor alpha (TNFalpha), soluble TNF-receptor p55 (sTNF-R)) and correlated the results with patient clinical outcome in terms of extent of pleural thickenings. We found pleural thickenings correlated with TGF-beta (p < 0.005) whereas no correlations could be observed with TNFalpha and sTNF-R. Further, we were interested in finding out how TGF-beta effects on fibroblast growth could be modulated. We found that pentoxifylline is able to inhibit both fibroblast proliferation and collagen synthesis independently of the stimulus. We conclude that, judging from in vitro studies, pentoxifylline might offer a new approach in the therapy of pleural as well as pulmonary fibrosis.


Tumour aneuploidy, prognostic parameters and survival in primary breast cancer.
Cellular DNA content of primary tumours from 280 patients with operable breast cancer was determined by flow cytometry using nuclei from paraffin sections stained with DAPI, and 199 of these patients were followed for 8-13 years after surgery. Tumours from 67 patients have also been analyzed for their DNA content using single cell suspensions from fresh tumour tissue stained with mithramycin and ethidium bromide, and the results compared with those obtained from paraffin blocks of the same tumours. Overall 60% of the tumours contained cells with abnormal DNA content (DNA-aneuploid populations). Survival and disease free interval were not significantly different in patients with DNA-diploid and DNA-aneuploid tumours when analysed by Mantel's life table method. There was however, an early advantage for patients with DNA-diploid tumours: during the first 30 months after surgery DNA-aneuploidy was associated with higher rate of recurrence and shorter survival. DNA-aneuploidy was strongly related to histological grade. Thus 11/49 (22%) grade I, 60/102 (59%) grade II, and 96/129 (74%) grade III tumours were DNA-aneuploid. Although there was no significant difference in survival of patients with DNA-diploid and DNA-aneuploid tumours overall, there appears to be an unexpected association between DNA-aneuploidy and better survival in grade II patients (P less than 0.01); a similar trend was observed for grade I patients. Although the proportion of DNA-aneuploid tumours was similar in oestrogen receptor positive and negative tumours, DNA-aneuploidy was associated with lower levels of oestrogen receptors in comparison to DNA-diploid tumours. Comparison between the modal DNA values of fresh and paraffin embedded samples showed high rate of comparability (64/67, P less than 0.0001).


What interventions do general practitioners recommend avoiding? A nationwide survey from Switzerland.
To address low-value interventions in healthcare, "Choosing Wisely" campaigns provide recommendations of interventions to avoid (RIAs). These are usually developed by expert panels rather than general practitioners (GPs). The aim of our study was to develop RIAs for ambulatory general medicine based on the suggestions of GPs, with their involvement from the very beginning. This was a nationwide online Delphi survey among Swiss Society of General Internal Medicine members. In round one, each participant suggested two interventions perceived as particularly inappropriate. In round two, the 16 most frequent RIAs were rated by importance on a 0–100 scale and compared with "Choosing Wisely" lists. We calculated descriptive statistics for suggestions and importance ratings, and used regression models to search for associations with GP characteristics. Response rates were 7.4% (538/7318) for round one and 18.2% (1357/7468) for round two. GPs provided 1074 suggestions. Out of the 16 most frequent RIAs, 13 corresponded to existing "Choosing Wisely" lists. The RIAs rated most important were: antibiotics in viral infections, unnecessarily duplicated tests and imaging in unspecific low back pain (means 88.5–91.7, standard deviations 18.6–19.9). None of the GPs' characteristics were associated with any of the five highest rated RIAs except for working in a hospital setting. Most RIA suggestions from GPs were concordant with previously published recommendations of interventions to avoid, independently of GPs knowledge of these and reflecting their high clinical relevance. In addition, our study revealed some more relevant topics and may help to develop future "Choosing Wisely" recommendations, with the final goal to reduce low-value care.


The effect of cyclophosphamide on immunological memory.
The intradermal injection of bovine gammaglobulin (BGG) anti-BGG immune complexes, in antibody excess, in Freund's complete adjuvant, induced strong delayed hypersensitivity and a state of priming which was recognized by an antihapten and anticarrier humoral immune response following injection of DNP9-BGG nine days later. Cyclophosphamide (CY), given either as small multiple doses over the first seven days after sensitization, or as a single dose on various days, had a strongly selective effect on the antihapten and anticarrier response. The drug treatment, using multiple doses, suppressed the development of a priming for the antihapten IgG2, but not for IgG1 production. Pretreatment with a large dose of CY (250 mg/kg) led only to an enhanced production of anti-DNP IgG2 and not of IgG1 antibodies. This suggests that CY inhibits the suppressor cells regulating the IgG2, but not the IgG1, antibody response. CY, given on day +3 but not on days 0 and +7 impaired both the IgG1 and the IgG2 response. Anticarrier-specific IgG1 could not be detected and the IgG2 was completely suppressed by the drug, given either as multiple doses or as a single large dose administered on days 0, +3 or +7. The selective influence of CY given about the time of the initial immunization suggests that the IgG1 and IgG2 responses involve memory cells with different susceptibilities to CY. Moreover, these memory cells appear to have a different susceptibility to CY as compared with that of the effector cells involved in delayed hypersensitivity.


Isolation of the phosphatidylinositol 4-monophosphate dissociable high-affinity profilin-actin complex.
Profilin was originally discovered in a tight complex with monomeric actin from bovine spleen, leading to its description as an actin monomer sequestering protein that maintains a pool of unpolymerized actin in cells. Subsequent purifications of profilin using different methods from diverse cells have consistently yielded preparations that affect the kinetics of actin assembly but do not efficiently maintain actin monomeric at steady state in solutions containing mM magnesium. Recent evidence that profilin inhibits phospholipase C and enhances nucleotide exchange of actin has led some to question whether profilin is ever truly an actin monomer sequestering agent. Here we report that the extraction of bovine spleen with fluoride- and pyrophosphate-containing solutions facilitates isolation of monomeric actin that is bound to profilin and does not polymerize in mM magnesium ion. The integrity of this complex depends on the presence of ATP. Phosphatidylinositol 4-monophosphate (PIP), previously shown to dissociate the low-affinity profilin-actin complex (Kd = 0.4 microM in mM Mg2+), also dissociates the high-affinity profilin-actin complex (Kd less than 0.02 microM in mM Mg2+) yielding actin that is polymerization competent and profilin that functions like profilins purified by conventional methods. Although the chemical basis of these results is not known, they indicate that profilin can tightly sequester actin monomers and support the earlier suggestion that the affinity of profilin for actin may be under metabolic control.


Molecular phylogeny and morphology of Carinadinium gen. nov. (Dinophyceae, Gonyaulacales), including marine sand-dwelling dinoflagellate species formerly classified within Thecadinium.
Thecadinium is a morphologically heterogenous marine benthic genus. Its polyphyly has been discussed. After redefinition of the sensu stricto genus, sensu lato taxa now need reclassification. Heterotrophic, morphologically closely related species were studied in detail. Molecular phylogenetic data for three of the four known species (T. ornatum, T. acanthium, T. ovatum) and new morphological data were obtained, leading to an emended thecal plate pattern, including the presence of an apical pore complex and an additional hypothecal plate. The results confirm the close relationship of the species and justify the description of Carinadinium gen. nov., characterized by the tabulation APC 3/4' 1/0a 6″ 6c 5s 5‴ 2'‴, an epithecal plate of special morphology, an apical flange, a ventral pore, antapical appendages, a descending cingulum and lateral cell flattening. The genus can be separated into two sub-clades, one with a third precingular 'dimple'-plate, four apical and no anterior intercalary plates and the other with a 'multi-pimple'-plate as third precingular or its homolog plate, three apical and one anterior intercalary plate. Carinadinium is phylogenetically related to the planktonic genera Protoceratium, Pentaplacodinium, and Ceratocorys (family Protoceratiaceae), and clearly belongs into the order Gonyaulacales, but with uncertain family affiliation.


Substitution of a hydrophobic residue alters the conformational stability of Shaker K+ channels during gating and assembly.
A leucine residue at position 370 (L370) in 29-4 Shaker K+ channels resides within two overlapping sequence motifs conserved among most voltage-gated channels: the S4 segment and a leucine heptad repeat. Here we investigate the effects observed upon substitution of L370 with many other uncharged amino acid residues. We find that smaller or more hydrophilic residues produce greater alterations in both activation and inactivation gating than does substitution with other large hydrophobic residues. In addition, subunits containing less conservative substitutions at position 370 are restricted in their assembly with wild-type subunits and are unlikely to form homomultimeric channel complexes. Consistent with the idea that L370 influences the tertiary structure of these channels, the results indicate that L370 undergoes specific hydrophobic interactions during the conformational transitions of gating; similar interactions may take place during the folding, insertion, or assembly of Shaker K+ channel subunits.


MicroRNA-related single-nucleotide polymorphism of XPO5 is strongly correlated with the prognosis and chemotherapy response in advanced non-small-cell lung cancer patients.
This study was performed to investigate if the microRNA-related single-nucleotide polymorphisms (miR-SNPs) of XPO5 gene predicted the prognosis and pathological features of advanced non-small-cell lung cancer patients receiving chemotherapy. A total of 131 advanced non-small-cell lung cancer (NSCLC) patients were recruited. MicroRNA (miRNA) binding site prediction software was adopted for the prediction and screening of SNPs in XPO5 and miRNA binding regions. Polymerase chain reaction (PCR) amplification was further performed. Time-dependent survival-free curves were constructed using the Kaplan-Meier technique. Univariate and the multivariate survival analyses were conducted for confirmation of prognostic factor for advanced NSCLC patients receiving chemotherapy. There were no significant differences of SNP distribution frequencies between groups, without statistical significance (P > 0.05). Included clinical pathological features and chemotherapy regimens showed no apparent statistical significance in influencing the curative effect of chemotherapy in advanced NSCLC patients (all P > 0.05). While the objective response rate (ORR) in patients who carried AA and AC genotype was 35.48 and 51.22 %, respectively, with statistically significant difference (P < 0.05). Univariate survival analysis indicated that patients who carried AA genotype showed a significantly lower 5-year survival rate to those who carried AC genotype (P < 0.05). And, considering pathological features, statistical significance was found in patients with different pathological types, lymph node metastasis, differentiation degree, T staging, and pathological staging (all P < 0.05). Multivariate analysis results indicated that the SNP sites of rs11077 might be an independent prognostic factor of advanced NSCLC patients receiving chemotherapy (risk ratio [RR] = 0.346; 95 % confidence interval [95 % CI] = 0.174-0.685, P = 0.002). Other clinical features were all considered to have no apparent effect in influencing the prognostic outcomes of advanced NSCLC patients receiving chemotherapy except lymph node metastasis (P < 0.05). miR-SNP rs11077 of XPO5 may be independently connected with the prognosis and chemotherapy response of advanced NSCLC patients, and patients with AC genotype have relatively improved prognostic outcomes and better curative effect of chemotherapy than those with AA allele of XPO5. Further, lymph node metastasis may be also involved in influencing the prognosis of advanced NSCLC patients.


New biologic agents and immunologic strategies.
The treatment of non-Hodgkin lymphoma has traditionally consisted of cytotoxic chemotherapy, which can frequently induce remissions but less reliably delivers long-term disease-free survival. The last two decades have heralded an era of increasing exploration of therapies derived from improved biologic understanding of tumors and tumor-host interactions, including the development of therapeutic tactics that take advantage of immune mechanisms to target and kill tumors. Foremost among these has been the development of monoclonal antibodies. Currently, an array of novel therapeutics in development may improve outcomes further, including novel monoclonals and other agents that take advantage of or optimize immune system function in the treatment of lymphoma or that provide other mechanisms of antitumor activity.


Mental health in schools.
The Comer School Development Program (SDP) has received considerable national attention over the last decade. The authors describe the origins, central tenets, and principles of the SDP. Although the Comer model is a systemic one, one of its primary foci is the developmental and mental health needs of children attending urban schools. The authors illustrate how teaching and consulting school faculty and parents about basic principles of development and psychopathology change the interaction between the child and adults who are important to the child. The authors contend that this step is an essential prerequisite for effective evaluation and treatment of children with possible psychiatric disturbances.


Matrix metalloproteinases and failed fracture healing.
During fracture healing and the resulting formation of new bone, an extensive amount of extracellular matrix is synthesized which subsequently undergoes enzymatic remodeling and then mineralization. The remodeling process of mostly collagenous molecules is largely attributable to matrix metalloproteinases (MMPs). A variety of members of this protease family and its respective inhibitors - termed tissue inhibitors of matrix metalloproteinases (TIMP) - have been found to be closely related to the fracture healing process. Delays in bone healing or even nonunion could be related to the concentrations of these enzymes or their behavior over time. In this study, serum samples were prospectively collected from patients who had undergone surgical treatment for limb fracture. Serum probes from 15 patients with nonunion of fractures 4 months after surgery have been compared to 15 matched patients with normal bone healing. Postoperative time courses of serum concentrations of MMP-1/-2/-3/-8/-9/-13 as well as TIMP-1/-2 were analyzed using commercially available enzyme immunoassays. Comparison between both collectives revealed significantly elevated serum concentrations of proMMP-1 in the nonunion group at 2 and 24 weeks after surgery. Similar findings were found for MMP-8 at 2, 4 and 8 weeks. At 1 week after surgery, TIMP-1 serum concentrations were significantly lower in nonunion patients when compared to patients with normal bone repair. We have been able to show for the first time the course of serum concentrations of MMPs and TIMPs during normal and delayed fracture healing. Characteristic time courses of systemic MMP- and TIMP-levels could be a reflection of local enzyme regulatory mechanisms during fracture healing. An altered balance of the MMP/TIMP system in favor of proteolytic activity as shown in our investigation may be involved in the pathophysiological processes leading to fracture nonunion.


Diagnosis and treatment of Epstein-Barr virus-associated natural killer cell lymphoproliferative disease.
Epstein-Barr virus (EBV) exhibits tropism for both lymphocytes and epithelial cells and can induce both replicative (productive/lytic) and latent (persistent) infections that result in a variety of human diseases. With regard to lymphocytes, latent EBV infection is linked to development of heterogeneous lymphoproliferative disease (LPD), such as B-cell LPD and T-cell/natural killer cell (T/NK cell) LPD. Unlike B-cell LPD, LPD derived from T-cells and NK cells sometimes has overlapping clinical symptoms, as well as histologic and immunophenotypic features, because both types of cells are derived from a common precursor. However, determination of cell lineage is important in classification of lymphoid neoplasms, and combined modern techniques allows us to distinguish NK cell LPD from T-cell LPD in most instances. Because NK cell LPD seems to be heterogeneous in terms of clinical features, prognosis, and diagnosis and has a monoclonal or polyclonal (or oligoclonal) nature, this review attempts to clarify recent research and clinical findings and to establish diagnostic and therapeutic strategies.


Carbon ions trigger DNA damage response to overcome radioresistance by regulating β-catenin signaling in quiescent HeLa cells.
Quiescent cancer cells are major impediments to effective radiotherapy (RT) and exhibit limited sensitivity to traditional photon therapy. Herein, the functional role and underlying mechanism of carbon ions in overcoming the radioresistance of quiescent cervical cancer HeLa cells were determined. Briefly, serum withdrawal was used to induce synchronized quiescence in HeLa cells. Quiescent HeLa cells displayed strong radioresistance and DNA repair potential. After irradiation with carbon ions, the DNA damage repair pathway may markedly rely on error-prone nonhomologous end-joining in proliferating cells, whereas the high-precision homologous recombination pathway is more relevant in quiescent cells. This phenomenon could be explained by the ionizing radiation (IR)-induced cell cycle re-entry of quiescent cancer cells. There are three strategies for eradicating quiescent cancer cells using high-linear energy transfer (LET) carbon ions: direct cell death through complex DNA damage; apoptosis via an enhanced mitochondria-mediated intrinsic pathway; forced re-entry of quiescent cancer cells into the cell cycle, thereby improving their susceptibility to IR. Silencing β-catenin signaling is essential for maintaining the dormant state in quiescent cells. Herein, carbon ions activated the β-catenin pathway in quiescent cells, and inhibition of this pathway improved the resistance of quiescent HeLa cells to carbon ions by alleviating DNA damage, improving DNA damage repair, maintaining quiescent depth, and inhibiting apoptosis. Collectively, carbon ions conquer the radioresistance of quiescent HeLa cells by activating β-catenin signaling, which provides a theoretical basis for improved therapeutic effects in patients with middle-advanced-stage cervical cancer with radioresistance.