Exploring invertebrate indicators of ecosystem health by focusing on the flow transitional zones in a large, shallow eutrophic lake.
The river-lake transitional zone provides a unique environment for the biological community and can reduce pollution inputs in lake ecosystems from their catchments. To explore environmental conditions with high purification potential in Lake Taihu and indicator species, we examined the river-to-lake changes in water and sediment quality and benthic invertebrate communities in the transitional zone of four regions. The spatial variations in the environment and invertebrate community observed in this study followed the previously reported patterns in Taihu; the northern and western regions were characterized by higher nutrient concentrations in water, higher heavy metal concentrations in sediment, and higher total invertebrate density and biomass dominated by pollution-tolerant oligochaetes and chironomids. Although nutrient concentrations were low and transparency was high in the eastern region, the taxon richness was the lowest there, which disagreed with the previous findings and might be due to a poor cover of macrophytes in this study. The river-to-lake change was large in the southern region for water quality and the invertebrate community. Water circulation induced by strong wind-wave actions in the lake sites of the southern region is assumed to have promoted photosynthetic and nutrient uptake activities and favored invertebrates that require well-aerated conditions such as polychaetes and burrowing crustaceans. Invertebrates usually adapted to brackish and saline environments are suggested to be indicators of a well-circulated environment with active biogeochemical processes and a less eutrophic state in Taihu, and wind-wave actions are key to maintaining such a community and natural purifying processes.


Attention problems in childhood and adult substance use.
To assess the link between childhood attention problems (AP) and substance use 18 years later. This cohort study was conducted in a community sample of 1103 French youths followed from 1991 to 2009. Exposures and covariates were childhood behavioral problems (based on parental report at baseline), early substance use, school difficulties, and family adversity. Outcome measures were regular tobacco smoking, alcohol problems, problematic cannabis use, and lifetime cocaine use (based on youth reports at follow-up). Individuals with high levels of childhood AP had higher rates of substance use (regular tobacco smoking, alcohol problems, problematic cannabis use, and lifetime cocaine use). However, when taking into account other childhood behavioral problems, early substance use, school difficulties, and family adversity, childhood AP were related only to regular tobacco smoking and lifetime cocaine use. Early cannabis exposure was the strongest risk factor for all substance use problems. This longitudinal community-based study shows that, except for tobacco and cocaine, the association between childhood AP and substance use is confounded by a range of early risk factors. Early cannabis exposure plays a central role in later substance use.


Benzocaine-Induced Methemoglobinemia: A Case Report.
Topical anesthetics, such as benzocaine, have been reported to cause methemoglobinemia, in which hemoglobin is unable to release oxygen effectively to body tissues. The pathophysiology, symptoms, and treatment of a 46-year-old patient are examined.


Serum 8-hydroxy-2-deoxyguanosine as a marker of DNA oxidative damage in horses with recurrent airway obstruction.
It has been reported that equine recurrent airway obstruction (RAO) is a state of oxidative stress. Oxidant-antioxidant imbalance is known to increase the conversion of deoxyguanosine to 8-hydroxy-2-deoxyguanosine (8-OHdG) in DNA. 8-OHdG can easily be measured using ELISA tests in serum or urine samples. In this study, we analysed serum 8-OHdG levels in horses with recurrent airway obstruction and in healthy controls. The study material consisted of seven healthy horses and seven horses with symptomatic RAO. All horses were exposed to moldy hay and straw for 48 h to induce clinical exacerbation of RAO. The serum 8-OHdG levels were determined using the ELISA Highly Sensitive 8-OHdG kit. The difference between the levels of 8-OHdG in healthy and RAO-affected horses was significant. The median level of 8-OHdG was 0.044 ng/ml in the healthy controls versus 0.498 ng/ml in RAO horses (P = 0.0021). The results of the study strongly suggest that DNA damage coexists in the course of equine RAO. We therefore propose that future research should aim at the development of new drugs that target pro-inflammatory molecules, since DNA damage appears to be the result of chronic inflammation.


Osteoporosis: intervention options.
Osteoporosis is a systemic progressive disease with important clinical complications because of the fractures that arise and cause major morbidity in especially the aging postmenopausal women. Because of the relative not complex procedure of diagnosis and prediction the most important question to answer: is treatment possible? There are now a variety of treatments available for the management of osteoporosis. The inhibitors of bone resorption, which include calcium, the vitamin Ds, bisphosphonates, calcitonins and gonadal steroids have been variously shown to prevent bone loss or to reduce fractures. On the other hand bone formation stimulating agents as fluorides and in the near future parathyroid hormone and analogues must be considered also. However, randomized clinical trials with fractures as clinical endpoints are only few in number and not present for every suggested treatment. During the last 3 years it has become clear that besides estrogen, bisphosphonates and now perhaps the selective estrogen receptor modulators also show a good alternative as intervention option of postmenopausal osteoporosis. At this moment sodium fluoride is not the first choice in treatment of osteoporosis in general practice.


Late complications following permanent pacemaker implantation or elective unit replacement.
To determine the rate of late complications following first implantation or elective unit replacement of a permanent pacemaker system. Analysis of pacemaker data and complications prospectively acquired on a computerised database. Complications were studied over an 11 year period from January 1984 to December 1994. Tertiary referral cardiothoracic centre. Records of 2621 patients were analysed retrospectively. Complications requiring repeat procedures occurring more than six weeks after pacemaker implantation or elective unit replacement. The overall rate of late complications was significantly lower after first implantation of a permanent pacemaker (34 cases, complication rate 1.4%, 95% confidence interval 0.9% to 1.9%) than after elective unit replacement (16 cases, complication rate 6.5% (3.3% to 9.7%). There were 20 cases of erosion, 18 infections, five electrode problems, and seven miscellaneous problems. Complications were more common with inexperienced operators (18.9% (6.0% to 31.8%)) than with experienced operators (0.9% (0.3% to 1.5%). The incidence of late complications following pacemaker implantation is low and compares favourably with early complication rates. The majority are caused by erosion and infection. Patients who have undergone elective unit replacement are at particular risk.


Myeloid cell subpopulations compensate each other for Ccr2-deficiency in glioblastoma.
Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology. We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages. We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations. These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.


How to become a pathogen.
For most bacterial species, virulence is viewed as a derived state, whereby pathogens acquire certain loci and are rendered virulent. The majority of virulence genes in Salmonella are present in closely related nonpathogenic species, and most genes known to be confined to the salmonellae are not essential for virulence. Alternative evolutionary scenarios may explain the origins of pathogenicity in Salmonella.


[Transfer of behavior patterns through transplantation of systems of neuroanatomic structures in amphibian larvae. II. Xenoplastic transplantation of hind brain systems between Xenopus laevis (Daud.) as well as Hymenochirus boettgeri (Torn.) and Triturus vulgaris].
By replacing parts of the neural plate (prospective medulla oblongata) of Triturus vulgaris by neural ectoderm of Xenopus laevis larval chimaeras were obtained, which showed donorlike rhythmical movements of distinct parts of the visceral musculature according to the place of implantation. Especially the branchial region with its external gills showed rhythmical movements and is the special object of this investigation.


Coronary artery bypass graft disease.
To review saphenous vein graft disease and its prevention and management. A MEDLINE search of articles published on saphenous vein and arterial bypass grafts. The reference sections of articles focused the selection of key studies. Relevant data representing key findings were noted. The outcome of coronary artery bypass grafting with the saphenous vein graft is unsatisfactory because vein grafts are prone to occlusive disease. By 10 years after surgery, 50% have closed, mainly because of atherosclerosis. With vein graft disease and graft closure, symptoms return. The best way to prevent vein graft disease is to use the internal mammary artery graft. This has become the preferred graft because it is not affected by atherosclerosis. Consequently, it has a much higher patency rate: 90% after more than 10 years. This provides such clinical benefits as decreased occurrence of symptoms, better left ventricular performance, decreased need for reoperation, and prolongation of life. The limited supply of mammary arteries has stimulated interest in identifying alternative arterial grafts. To prevent vein graft disease, surgeons should bypass diseased coronary arteries with at least one arterial graft and take measures during the surgery to avoid endothelial injury to vein grafts. Treatment with antiplatelet agents decreases the vein graft occlusion rate. When graft atherosclerosis causes symptoms, reoperation will probably prolong life if an old graft to the left anterior descending coronary artery is diseased. Reoperation increases a patient's chance for survival if the surgeon uses at least one arterial graft.


Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial.
Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects. This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of < or =10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ). Adjunctive quetiapine (mean dose 386mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8+/-9.0) to week 12 (9.0+/-10.2) (-20.6; p<0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5kg at week 12) or laboratory assessments. The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.


Comprehensive management of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease that poses a myriad of clinical problems. Patients with ALS are best treated in a multidisciplinary setting involving physicians, clinical nursing specialists, and physical, occupational, speech, and respiratory therapists, as well as psychologists and social workers. Palliative and rehabilitative strategies may ease suffering, while new treatments provide hope for effective treatment of this disease.


Influence of the apical enlargement size on the endotoxin level reduction of dental root canals.
Gram-negative bacteria play an essential role in endodontic infections because they have virulence factors such as endotoxin. Due to its potential cytotoxic activity, special attention has been given to the removal/neutralization of this endotoxin in the root canal system. The aim of this study was to evaluate the influence of the apical enlargement size (AES) by using rotary instruments on the endotoxin level reduction of dental root canals. Forty root canals of the mandibular premolar teeth were used. Escherichia coli endotoxin (055: B55) was inoculated into thirty root canals. Ten teeth served as the negative control group. After the incubation period, the first endotoxin samples were collected from the root canals with a sterile/apyrogenic paper point for the analysis of the endotoxin units (EU/mL) present before instrumentation (S1). Specimen instrumentation was performed with the Mtwo rotary system in the sequence 10/.04, 15/.05, 20/.06, 25/.06, 30/.05, 35/.04 and 40/.04. To monitor the effectiveness of increasing apical enlargement on endotoxin removal, the second endotoxin samples were collected from all the root canals after instrumentation with the following instruments: #25/.06--(S2); #30/.05--(S3); # 35/.04--(S4); and #40/.04--(S5). Limulus amebocyte lysate (LAL) was used to quantify the levels of endotoxin. The results were statistically compared by using repeated measures of ANOVA with post hoc Tukey testing. Increasing levels of endotoxin removal was achieved by large sized apical enlargement: S2 (AES #25/.06)--89.2%, S3 (AES #30/.05)--95.9%, S4 (AES #35/.04)--97.8% and S5 (AES #40/.04)--98.2%. Substantial reduction of endotoxin content was obtained in S4 and S5 compared to S2 (p<0.05), however, the root canal preparation was not able to eliminate the endotoxin. Under the conditions of this study, it was concluded that the reduction of endotoxin levels of the dental root canals could be predicted by increasing the apical enlargement size.


The Effects of Propofol Anesthesia on Lipid Profile and Some Biochemical Indices in Cats.
The aim of the present study was to evaluate lipid profile (triglyceride, total cholesterol, HDL, LDL, and VLDL), pancreas (lipase and amylase), liver (AST, ALT, and ALP), blood urea nitrogen, creatinine, uric acid, sodium and potassium function indicators in cats undergoing two different durations of anesthesia with propofol. Ten adult female cats were randomly divided into two groups (n= 5) and anaesthetized with propofol 1% (induction: 8 mg/kg; infusion: 0.3 mg/kg/min) for either 45 or 90 minutes. Blood samples were collected at predetermined intervals up to 72 hours later. Comparison of the measured variables between treatments did not show significant differences. Triglyceride and cholesterol levels showed significant increase after induction of anesthesia (P < .05). The highest triglyceride and cholesterol values were recorded at 6 and 24 hours. HDL was lower while LDL and VLDL were higher at several time points after anesthesia (P < .05). Higher values of lipase, ALT and AST were detected after induction (P < .05). All the observed alterations were within normal ranges. In conclusion, propofol anesthesia was associated with some changes in lipid profile, as well as pancreatic and liver function indices, which should be considered in clinical situations. It seems that in the absence of pre- or co-existing disturbances, induction and maintenance of anesthesia with propofol did not carry additional risk to cats.


"Rescue administration" of intracoronary thrombolytic therapy for drug-eluting stent thrombosis.
Stent thrombosis is an example of device-induced, platelet-mediated arterial thrombosis with a potentially fatal adverse event that often leads to myocardial infarction and/or death. The optimal treatment of patients with drug-eluting stent thrombosis in whom mechanical thrombectomy has failed is not established. This case demonstrates the usefulness of intracoronary thrombolysis after failed mechanical thrombectomy in patients with stent thrombosis. To our knowledge, this is the first report on using intracoronary thrombolysis in this specific situation.


Drug-drug interactions among recently hospitalised patients--frequent but mostly clinically insignificant.
Patients use and store considerable amounts of drugs. The aim of the present study was to identify potential drug-drug interactions between drugs used by patients recently discharged from the hospital and, subsequently, to estimate the clinical implications of these interactions. Patients were visited within 1 week following their discharge from hospital and interviewed about their drug use. Stored products were inspected. We used a bibliography (Hansten and Horn; Wolters Kluwer Health, St. Louis, Mo., 2004) to identify and classify potential drug-drug interactions. In total, 83 surgical and 117 medical patients (n = 200) were included in the survey, of which 139 (70%) were women. The median age was 75 years (range: 24-100 years). Patients stored 2119 medications at home (median: nine per patient; range: 2-44) and used 1622 medications daily or on demand (median: eight per patient; range: 1-24). With respect to those drugs used daily or on demand, 476 potential interactions were identified (126 patients); none were class 1 (always avoid drug combination) and 25 were class 2 (usually avoid combination; 24 patients). Eleven of the potential class 2 interactions involved over-the-counter products (aspirin and ginkgo biloba). Of the 52 drugs involved in potential class 2 interactions, 50 had been used for more than 1 month. According to the hospital case notes, none of the potential class 2 interactions had actually caused adverse effects. Although potential drug-drug interactions are highly prevalent, serious and clinically significant interactions are rare among recently hospitalised patients.


Comparing the Efficacy and Safety of Direct Oral Anticoagulants With Warfarin in the Morbidly Obese Population With Atrial Fibrillation.
The International Society of Thrombosis and Haemostasis recommends avoiding direct oral anticoagulants (DOACs) in morbidly obese patients with a body mass index (BMI) >40 kg/m2 or weight >120 kg because of limited clinical data in this group of patients. The objective of this study was to evaluate the efficacy and safety of DOACs in morbidly obese patients with atrial fibrillation or flutter. A retrospective, single-center cohort study was conducted of patients older than 18 years, with BMI >40 kg/m2 or weight >120 kg, who were diagnosed as having atrial fibrillation or flutter and who received warfarin or DOACs (ie, dabigatran, rivaroxaban, or apixaban). The primary efficacy outcome was the incidence of ischemic stroke or transient ischemic attack (TIA), whereas the primary safety outcome was the incidence of major bleeding. A total of 64 patients in each group were included in the study analysis. The incidence rate of ischemic stroke or TIA was 1.75%/year in the DOAC group compared with 2.07%/year in the warfarin group (rate ratio = 0.84; 95% CI = 0.23 to 3.14; P = 0.80). The incidence rate of major bleeding was 2.18%/year in the DOAC group, compared with 4.97%/year in the warfarin group (rate ratio = 0.44; 95% CI = 0.15 to 1.25; P = 0.11). Conclusion and Relevance: Apixaban and rivaroxaban may be considered as alternatives to warfarin for atrial fibrillation or flutter in morbidly obese patients. Dabigatran use in morbidly obese patients needs caution until further studies are conducted.


According to him: barriers to healthcare among African-American men.
We sought to elicit barriers to health and primary healthcare use among African-American men residing in a low-income, urban area. We conducted a qualitative study of African-American men using focused group interviews. A purposive sampling technique was used to recruit 8 select subgroups: adolescents (age 16-18), trauma survivors, HIV-positive men, homeless men, men who have sex with men (MSM), substance abusers, church affiliated men and a mixed sample (N=71). Focus groups were moderated by trained, African-American male focus group leaders. Qualitative analysis of focused group transcripts yielded 2 major categories-intrinsic barriers and extrinsic barriers. Within the intrinsic barriers category, 5 subcategories emerged: lack of health awareness, fear, healthcare as needed, medical mistrust and fatalism. Extrinsic barriers included cost/benefit, clinic experience, and cultural and linguistic differences. Participants also offered solutions to address key barriers. African-American men identified key intrinsic and extrinsic barriers to health and primary healthcare, including lack of health awareness and providers' cultural and linguistic differences. These barriers constitute important areas of future research and intervention to address African-American men's health and willingness to seek healthcare.


TELEMAM: a cluster randomised trial to assess the use of telemedicine in multi-disciplinary breast cancer decision making.
The TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs). Over 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of 'in-person' meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach. Levels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year. Telemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard 'in-person' meetings.


Characteristics and response cutoff of octreotide suppression test in thyrotrophin (TSH)-secreting pituitary adenomas.
Somatostatin analogs are recommended for preoperative therapy in thyrotrophin secreting pituitary adenomas (TSHomas). Octreotide suppression test (OST) was designed to differentiate TSHomas with resistance to thyroid hormones, while its ability to test the sensitivity of SSA has not been fully studied. To test the sensitivity of SSA in TSHomas with OST. We collected 48 pathologically confirmed TSHoma patients with complete 72 h' data of OST into analysis. Octreotide suppression test. Sensitivity timepoint and cutoff of OST. During the entire OST, the TSH descended maximally 89.07% (73.85%, 96.77%), while the FT3 and FT4 declined slowly [43.40% (37.80%, 54.44%) and 26.59% (19.01%, 33.13%), respectively]. The 24th hour was the timepoint wherein the stability occurs for TSH, and the 48th hour for FT3 and FT4 during OST. In the patients who received both short- and long-acting somatostatin analogs (SSA), the 24-h timepoint was the most predictive timepoint for the percentage of TSH decline (Spearman's rank correlation analysis, r = .571, p < .001), while the 72-h timepoint was optimal for predicting the magnitude of TSH decline (Spearman's rank correlation analysis, r = .438, p = .005). In the 24th timepoint, a positive correlation was also observed between TSH suppression rate and the percentage decrease and absolute value decrease of FT3 and FT4. Furthermore, in patients treated with long-acting SSA, the 72-h timepoint was optimal for predicting both the percentage (Spearman's rank correlation analysis, r = .587, p = .01) and magnitude (Spearman's rank correlation analysis, r = .474, p = .047) of TSH decline. The 24th hour was the optimal timepoint with 44.54% (50% of median value of TSH in 72-hOST) decrease of TSH being the observing cutoff. The adverse effect of OST was predominantly occurred in the gastrointestinal system and no severe event occurred during OST. Paradoxical response could occur in OST and it did not influence the effect of SSA as long as sensitivity was confirmed. A high level of hormonal control was achieved in the SSA-sensitive patients. OST can be used as an efficient tool to guide the adequate use of SSA.


Deep sedation in pediatric imaging: efficacy and safety of intravenous chlorpromazine.
The quality of MRI and CT depends largely on immobility of the patient during the procedure, which is often difficult to achieve without sedation in children below the age of 6 years. To assess the efficacy and safety of intravenous chlorpromazine sedation for repeated imaging in young children treated for cancer. From July 2003 to January 2007, information on children younger than 6 years of age having MRI or CT was prospectively collected. Forty-five minutes before the scan, a 10-min infusion of chlorpromazine 0.5 mg/kg was administered and managed by non-anesthetic staff. Patient monitoring included continuous measurement of pulse, respiration, oxygen saturation and arterial blood pressure. Procedure-related parameters and adverse events were documented. Sedation was considered successful when the procedure was completed and at least 95% of images were usable. One-hundred-one procedures (82 MRI, 19 CT) were evaluated in 62 children, 3-74 months old. Adequate sedation was achieved in 96% of cases, with mean induction time, 22 min; mean duration of sleep, 72 min, and mean duration of procedure, 33 min. Mean time spent in the radiology unit was 104 min. Ninety-six percent of imaging procedures were successfully completed. No cardiac, respiratory, neurological or allergic complication occurred. Intravenous chlorpromazine is safe and effective for procedural sedation in young children with cancer undergoing MRI and CT.


Antibody response to pneumococcal vaccination as a function of preimmunization titer.
The interpretation of an adequate response to the unconjugated 23-valent pneumococcal vaccine for serotypes having high preimmunization titers remains challenging. We sought to determine whether high preimmunization titers preclude a 4-fold or greater response to vaccination. Moreover, we sought to determine the effect of the following covariates on this response: absolute preimmunization titer value, age, sex, serum IgG level, and serum IgG subclasses. We conducted a retrospective analysis of patients who were seen in our immune disorders clinic between 2001 and 2007 who had received the unconjugated 23-valent pneumococcal vaccine. Logistic regression was used to estimate the effect of different covariates, including preimmunization titer values, age, sex, IgG levels, and IgG subclass values, on the odds of a 4-fold or greater antibody response. Per serotype, 10% to 40% of subjects with a high preimmunization titer attained at least a 4-fold response to vaccination. However, the odds of a 4-fold or greater response were found to decrease as a function of the absolute preimmunization titer value with an absolute value for each serotype beyond which the odds ratio approached zero. High pneumococcal preimmunization titers do not necessarily preclude a 4-fold or greater response to vaccination. However, there appear to be serotype-specific preimmunization titer values, ranging from 4.4 to 10.3 microg/mL, above which a 4-fold or greater response would not be expected. This response does not seem to be significantly affected by age, sex, IgG level, or IgG subclass value.


A mechanism for valine-resistant growth of Escherichia coli K-12 supported by the valine-sensitive acetohydroxy acid synthase IV activity from ilvJ662.
Acetohydroxy acid synthase (EC 184.108.40.206; AHAS) isozymes I and III are expressed in Escherichia coli strain K-12 and, when inhibited by L-valine, cannot support cell growth. AHAS IV, expressed from mutation at ilvJ662, exhibits valine-sensitivity similar to that of AHAS III, yet AHAS IV does support cell growth in valine minimal medium. Rate equations were derived for AHAS III and AHAS IV reaction in crude extracts and for partially purified AHAS IV. Values of kinetic constants in these equations were determined in order to model a probable reaction mechanism. Computer modeling of initial velocity reactions at physiological substrate concentrations simulated consequences of valine-inhibition and revealed that AHAS IV synthesized AHB at a maximal rate over four times faster than AHAS III under these conditions. The simulations predicted that cells depending upon AHAS III for growth in valine minimal medium would accumulate higher levels of 2-ketobutyrate than cells using AHAS IV. Experiments on growth inhibition by valine revealed more than a five-fold difference in 2-ketobutyrate accumulation, thus confirming these predictions. These data support the hypothesis that valine inhibition of growth is a consequence of 2-ketobutyrate accumulation to toxic levels. We propose that the valine-inhibited AHAS IV activity prevents growth inhibition by keeping 2-ketobutyrate accumulation to a lower level than resulting from AHAS III activity.


A mean shift algorithm for drift correction in localization microscopy.
Single-molecule localization microscopy techniques transcend the diffraction limit of visible light by localizing isolated emitters sampled stochastically. This time-lapse imaging necessitates long acquisition times, over which sample drift can become large relative to the localization precision. Here, we present an efficient and robust method for estimating drift, using a simple peak-finding algorithm based on mean shifts that is effective for single-molecule localization microscopy in two or three dimensions.


Sex-Specific Epigenetics: Implications for Environmental Studies of Brain and Behavior.
This review discusses the current state of knowledge on sex differences in the epigenetic regulation in the brain and highlights its relevance for the environmental studies of brain and behavior. Recent evidence shows that epigenetic mechanisms are involved in the control of brain sexual differentiation and in memory-enhancing effects of estradiol in females. In addition, several studies have implicated epigenetic dysregulation as an underlying mechanism for sex-specific neurobehavioral effects of environmental exposures. The area of sex-specific neurepigenetics has a great potential to improve our understanding of brain function in health and disease. Future neuropigenetic studies will require the inclusion of males and females and would ideally account for the fluctuating hormonal status in females which is likely to affect the epigenome. The implementation of cutting-edge methods that include epigenomic characterization of specific cell types using latest next-generation sequencing approaches will further advance the area.


Clinical trials for preventing post stroke cognitive impairment.
Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimer's disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed.


Modelling spatial and temporal variations in the water quality of an artificial water reservoir in the semiarid midwest of Argentina.
Temporal and spatial patterns of water quality of an important artificial water reservoir located in the semiarid Midwest of Argentina were investigated using chemometric techniques. Surface water samples were collected at 38 points of the water reservoir during eleven sampling campaigns between October 1998 and June 2000, covering the warm wet season and the cold dry season, and analyzed for dissolved oxygen (DO), conductivity, pH, ammonium, nitrate, nitrite, total dissolved solids (TDS), alkalinity, hardness, bicarbonate, chloride, sulfate, calcium, magnesium, fluoride, sodium, potassium, iron, aluminum, silica, phosphate, sulfide, arsenic, chromium, lead, cadmium, chemical oxygen demand (COD), biochemical oxygen demand (BOD), viable aerobic bacteria (VAB) and total coliform bacteria (TC). Concentrations of lead, ammonium, nitrite and coliforms were higher than the maximum allowable limits for drinking water in a large proportion of the water samples. To obtain a general representation of the spatial and temporal trends of the water quality parameters at the reservoir, the three-dimensional dataset (sampling sites×parameters×sampling campaigns) has been analyzed by matrix augmentation principal component analysis (MA-PCA) and N-way principal component analysis (N-PCA) using Tucker3 and PARAFAC (Parallel Factor Analysis) models. MA-PCA produced a component accounting for the general behavior of parameters associated with organic pollution. The Tucker3 models were not appropriate for modelling the water quality dataset. The two-factor PARAFAC model provided the best picture to understand the spatial and temporal variation of the water quality parameters of the reservoir. The first PARAFAC factor contains useful information regarding the relation of organic pollution with seasonality, whereas the second factor also encloses information concerning lead pollution. The most polluted areas in the reservoir and the polluting sources were identified by plotting PARAFAC loadings as a function of the UTM (Universal Transverse Mercator) coordinates.


Comparative studies on group III σ-hole and π-hole interactions.
The σ-hole of M2 H6 (M = Al, Ga, In) and π-hole of MH3 (M = Al, Ga, In) were discovered and analyzed, the bimolecular complexes M2 H6 ···NH3 and MH3 ···N2 P2 F4 (M = Al, Ga, In) were constructed to carry out comparative studies on the group III σ-hole interactions and π-hole interactions. The two types of interactions are all partial-covalent interactions; the π-hole interactions are stronger than σ-hole interactions. The electrostatic energy is the largest contribution for forming the σ-hole and π-hole interaction, the polarization energy is also an important factor to form the M···N interaction. The electrostatic energy contributions to the interaction energy of the σ-hole interactions are somewhat greater than those of the π-hole interactions. However, the polarization contributions for the π-hole interactions are somewhat greater than those for the σ-hole interactions.


Uncemented, curved, short endoprosthesis stem for distal femoral reconstruction: early follow-up outcomes.
Uncemented endoprosthetic knee replacement has become a mainstream treatment for malignant tumours of the distal femur. Most femoral stems, however, are straight and therefore poorly fit the anteriorly bowed curvature of the femur. To address this issue, we used a short, curved, uncemented press-fit femoral stem and evaluated its short-term outcomes after reconstruction of the distal femur. Forty-two patients underwent distal femur replacement using curved press-fit stem. To assess the interface, we measured the axial length of the press-fit area and the perpendicular distance of the radiolucent area between the stem and bone on digital images obtained using tomosynthesis with Shimadzu Metal Artefact Reduction Technology (T-SMART). Postoperative complications and oncological outcomes were monitored at each follow-up visit. Of the 42 patients enrolled in the study, two had cancer-related deaths and one had local tumour recurrence. The minimum follow-up time of the surviving patients was 24 months, with no incidence of aseptic loosening or mechanical failure of the prosthesis. The average effective contact length between the press-fit stem and bone was 74.0 mm, with nearly undetectable radiolucent gaps between the implant and the bone on medial-lateral and anteroposterior views. Over the short term, uncemented, curved, short stem provides a stable bone-prosthesis interface without any aseptic loosening.


Prevalence and correlates of false-positive results after 3-D screening mammography among uninsured women in a community outreach program.
False-positive results have been rarely investigated among uninsured minority women who undergo 3-D screening mammography. Here, we analyzed data from 21,022 women participating in the Breast Screening and Patient Navigation (BSPAN) program of North Texas with an aim to report prevalence and correlates of false-positive results after 3-D screening mammography, stratified by age. False-positives were defined as a negative diagnostic mammogram or a negative biopsy within 1 year of a positive screen. We used multivariable logistic regression to assess associations of demographic and clinical covariates and false positive results for age groups 40-49 and 50-64 years. Prevalence of false-positive results was 11.8% and 9.6% in the 40-49 and 50-64 age groups, respectively. Multivariable logistic regression demonstrated that, in the 40-49 age group, women who were non-menopausal, did not use hormone replacement therapy (HRT), and had self-reported prior mammograms had higher odds of false-positive results than those who were menopausal, used HRT and had no self-reported prior mammograms, respectively. In the 50-64 age group, women with a prior self-reported diagnostic mammogram had higher odds of false-positive results than those without a prior self-reported diagnostic mammogram. This study establishes contemporary evidence regarding prevalence and correlates of false-positive results after 3-D mammography in the unique BSPAN population, and demonstrate that use of 3-D mammography is not enough to reduce false-positive rates among uninsured women served through community outreach programs. Further research is needed to explore improved techniques to reduce false-positive rates, and ensure optimal use of scarce resources in outreach programs.


Granisetron in the control of radiotherapy-induced nausea and vomiting: a comparison with other antiemetic therapies.
Radiotherapy-induced nausea and vomiting (RINV) can be one of the most distressing symptoms of radiotherapy treatment, which if incompletely controlled may last for several weeks with fractionated radiotherapy and prevent completion of the planned treatment course. Current treatment guidelines recommend the use of 5-HT(3) receptor antagonists with or without corticosteroids for highly and moderately emetogenic radiotherapy, though only granisetron and ondansetron are currently indicated for RINV in most countries. Granisetron is a potent and highly selective 5-HT(3) receptor antagonist, with demonstrated efficacy in RINV in both placebo-controlled and comparative studies. In this paper the clinical experience with granisetron in RINV is reviewed, and its efficacy and safety compared with other antiemetic therapies.


Activation of cannabinoid CB1 receptors in the ventral hippocampus improved stress-induced amnesia in rat.
The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories. The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats. In order to induce acute stress, the animals were placed on an elevated platform for different time periods (10, 20 and 30min). Our results indicated that post-training 20 and 30min exposure to stress, but not 10min, induced amnesia. Post-training microinjection of a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 2.5-7.5ng/rat) into the VH (intra-VH) induced amnesia. Interestingly, post-training intra-VH microinjection of the same doses of ACPA improved stress-induced amnesia. On the other hand, post-training intra-VH microinjection of a selective CB1 receptor antagonist, AM-251 (20-50ng/rat) with exposure to an ineffective stress (10min) potentiated the effect of stress on memory consolidation and induced amnesia. It should be noted that post-training intra-VH microinjection of the same doses of AM-251 alone had no effect on memory consolidation. Our results revealed that post-training intra-VH microinjection of AM-251, prior to ACPA microinjection, inhibited the reversal effect of ACPA on acute elevated platform stress. Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors.


Pyrazoles and pyrazolines as neural and inducible nitric oxide synthase (nNOS and iNOS) potential inhibitors (III).
We have previously described a series of 4,5-dihydro-1H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1H-pyrazole and 1-alkyl-3-benzoyl-1H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1H-pyrazole-5-carboxylic acid ethyl ester derivative (10l), which shows an inhibition of 50% versus iNOS at a 1mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies.


Using weighted communication scoring procedures in naturalistic play samples: Preliminary validation in preschool-aged boys with autism or fragile X syndrome.
In the present study, we provide a preliminary evaluation of the validity and reliability of using weighting procedures to measure communication in play samples for preschool-aged boys with autism or fragile X syndrome (FXS). Because weighting procedure communication scores (WPCSs) reflect growth in both communicative frequency and complexity, establishing the psychometrics of the component scores, in addition to the overall metric, affords investigators the opportunity to describe growth within and across skills. Results, for both groups, provide support regarding the psychometric appropriateness (i.e., convergent validity, divergent validity, and internal consistency) for all WPCSs. That said, a trend was observed for reliability scores to be slightly lower or more variable in boys with autism than in boys with FXS. Finally, although significant associations were observed in the associations between WPCSs across play contexts, contexts effects were observed for all three WPCSs. Together, results from this study provide promising preliminary data indicating the utility of using WPCSs in children with neurodevelopmental disabilities. Lay Summary: Language supports long-term positive outcomes; it is important to identify accurate and flexible ways of measuring language in children over time. We considered the effectiveness of using a procedure that considers changes in the number of communication acts and the types of acts produced during a play session by preschool-aged boys with autism or fragile X syndrome. These procedures were found to be valid and reliable.


Synthesis and cytotoxicity studies of bifunctional hybrids of nitrogen mustards with potential enzymes inhibitors based on melamine framework.
The new class of hybrid anticancer drugs were obtained by selective functionalization of the triazine scaffold. These were prepared by rearrangement of mono-, bis- and/or tris-(1,3,5-triazin-2-yl)-1,4-diazabicyclo[2.2.2]octanium chlorides leading to formation of 2-chloroethylamino fragments attached to 1,3,5-triazine via one, two or three piperazine rings respectively. Their inhibitory effect was found strongly dependent on the structure of substituents in triazine ring. The anti-proliferative activity of the hybrids evaluated in vitro by using mammalian tumour cells estimated as IC(50) was in the range 0.62-139,78 µM. Both cytotoxicity and alkylating activity depended on the substituents of triazine ring, however, also the mono-functional analogues of nitrogen mustards, which are unable to form liaisons between two DNA strands, induced apoptosis and necrosis in the tested cells.


Facile synthesis of hybrid sulfonophosphinodipeptides composing of taurines and 1-aminoalkylphosphinic acids.
Both sulfonopeptides and phosphonopeptides are important analogs of naturally occurring peptides and have been widely used as enzyme inhibitors and haptens for producing catalytic antibodies due to their tetrahedrally structural features. A series of hybrid sulfonophosphinodipeptides composing of taurines and 1-aminoalkylphosphinic acids were first and conveniently synthesized in satisfactory to good yields via a Mannich-type reaction of N-benzyloxycarbonylaminoalkanesulfonamides, aldehydes, and aryldichlorophosphines, and subsequent hydrolysis. The current method provides an efficient and direct synthesis of hybrid sulfonophosphinodipeptides.


An update to the National Cholesterol Education Program: 2009 suggested changes.
In view of new, robust data published after the publication of the NCEP-ATP III in 2001, I am proposing a more aggressive management of cholesterol. Lower LDL-C levels must be achieved to stop and regress atherosclerosis and further reduce cardiovascular mortality.


Imaging of the heart with computed tomography.
Imaging of the heart with computed tomography (CT) was already introduced in the 1980Is and has meanwhile entered clinical routine as a consequence of the rapid evolution of CT technology during the last decade. In this review article, we give an overview on the technology and clinical performance of different CT-scanner generations used for cardiac imaging, such as Electron Beam CT (EBCT), single-slice CT und multi-detector row CT (MDCT) with 4, 16 and 64 simultaneously acquired slices. We identify the limitations of current CT-scanners, indicate potential of improvement and discuss alternative system concepts such as CT with area detectors and dual source CT (DSCT).


Influence of leucine infusion on intracellular amino acids in humans.
A continuous intravenous infusion of L-leucine (300 mumols min-1) was given to 12 healthy females over a 2 1/2 h period. Arterial plasma concentrations of amino acids and the keto acids of the branched-chain amino acids (BCAA) were measured. In six subjects muscle biopsies were taken before and at the end of the infusion for determination of intracellular (i.c.) free amino acid concentrations, and leg exchange of amino acids was measured. During infusion the plasma level of leucine rose sixfold. Approximately 40% of the infused amount was taken up by muscle. Of this, half was accumulated intracellularly, where the free leucine concentration increased from basal 190 +/- 22 to 580 +/- 110 mumols l-1 ICW (intracellular water) at the end of infusion. The concentrations of most other amino acids, above all the other BCAA and the aromatic amino acids, decreased, by 17-48% in the i.c. pool and by 17-79% in plasma. The plasma level of ketoisocaproic acid (KIC), the keto acid of leucine, increased in parallel with that of leucine. The concentration of keto valine, ketoisovaleric acid (KIV), decreased by 75%, whereas the keto acid of isoleucine, ketomethylvaleric acid (KMV), was unchanged. Leg release of alanine decreased significantly, whereas the exchange of other amino acids were unchanged. Taken together, decreased i.c. and plasma concentrations but unchanged leg exchange of tyrosine and phenylalanine suggest i.c. accumulation of protein. It can be calculated that approximately 40% of the leucine taken up by muscle was accumulated in the intracellular free pool, some 20% could have been incorporated into protein and 40% was probably oxidized.


Treatment of Khat Addiction with Bromocriptine Mesylate: A Case Report and Review of Cocaine- and Amphetamine-Like Effects.
A patient addicted to khat was successfully treated as an outpatient. He was detoxified with bromocriptine mesylate 1.25 mg. q 6 h which was titrated downward over 4 weeks. Khat is a bush historically indigenous to the Mideast. It has high addictive potential due to its constituent, "cathinone." Cathinone, (1(5) + (minus sign) aminopropiophenon), is a sympathomimetic, similar but not identical to cocaine and amphetamine in activity and addiction potential. Bromocriptine has been extensively reported to successfully detoxify cocaine addiction and could be useful in khat addiction.


A Focus on Maternal Health Before Assisted Reproduction: Results From a Pilot Survey of Canadian IVF Medical Directors.
To describe current physician practice patterns in Canada with regard to performing in vitro fertilization in high-risk patients. All medical directors of IVF clinics registered with the Canadian Fertility and Andrology Society (n=35) were invited to participate in an online survey between January and May 2014. We carried out descriptive analyses of participants' responses regarding implementation of local restrictive policies for access to IVF. Whether practice patterns differed in hospital versus community-based clinics was assessed using chi-square testing with significance set at alpha<0.05. The response rate was 77.1%. More than one half of clinics (55.6%) were university-affiliated, and 29.6% were hospital-based. The majority of respondents (70.4%) used an upper age limit for permitting IVF (median 50 years, IQR 44 to 50), mostly because of lower pregnancy and live birth rates. Approximately one half of respondents limited treatment according to BMI (median upper permitted BMI 38 kg/m2, IQR 35 to 40 kg/m2) to minimize complications during pregnancy. Most respondents (77.8%) believed that routine pre-IVF medical assessment would be useful in their daily practice. There was a non-significant trend towards more restrictive policies in hospital-based clinics compared with community-based clinics. Our findings confirm that Canadian reproductive medicine physicians are taking maternal health factors into consideration when assessing patients' suitability for IVF. Nevertheless, there is between-clinic variability in the parameters used to assess eligibility for treatment. In light of the changing maternal demographic, more research is needed on assisted reproductive technology and perinatal outcomes in women who are at risk for pregnancy complications.


Similar outcomes between two-stage revisions for infection and aseptic hip revisions.
Two-stage revision hip arthroplasty using an antibiotic-loaded spacer is the most widely performed procedure for infected hip arthroplasties. The clinical outcome of this type of surgery compared with aseptic joint revision with exchange of femoral and acetabular components is still controversial due to the relative lack of medium- to long-term follow-up. Therefore, we analysed clinical and radiological outcomes of septic two-stage revisions compared with aseptic hip revision surgeries. In this retrospective study we assessed 82 consecutive patients who underwent two-stage revision for septic total hip (45 patients) or one-stage aseptic revision arthroplasty (37 patients). The average follow-up was 53 months for the aseptic group and 55 months for the septic group. For clinical evaluation, we used the Harris Hip Score (HHS) and the Merle d'Aubigné and Postel score. The postoperative pain level was determined with the visual analogue pain scale. The surgeries were performed 124 months (aseptic group) and 119 months (septic group) after primary total hip arthroplasty on average. The main indications for aseptic revision surgeries were aseptic loosening (96%), dislocation (2.2%), and periprosthetic fracture (2.2%). In the clinical outcome patients achieved 75.5 points in the aseptic group and 73.4 points in the septic group in the Harris Hip Score. The Merle d'Aubigné and Postel Score revealed 12.5 points for the aseptic group and 13.1 points for the septic group. Mean level of persisting pain was 0.8 (aseptic group) and 0.4 (septic group) on the visual analogue scale (VAS). Overall survival in the aseptic group was 85.6% at 9.8 years 82.7% at 10.1 years for the septic group, with a repeat revision rate of 8.1% and 6.7%, respectively. Performing aseptic acetabular and femoral revision hip arthroplasty showed equal clinical outcomes in relation to septic two-stage revision hip surgeries. Our results showed a tendency for better outcome in comparison with the information given in the literature for septic and nonseptic exchange arthroplasties, including a lower rate of re-revisions.


btn1 affects endocytosis, polarization of sterol-rich membrane domains and polarized growth in Schizosaccharomyces pombe.
btn1, the Schizosaccharomyces pombe orthologue of the human Batten disease gene CLN3, exerts multiple cellular effects. As well as a role in vacuole pH homoeostasis, we now show that Btn1p is essential for growth at high temperatures. Its absence results in progressive defects at 37 degrees C that culminate in total depolarized growth and cell lysis. These defects are preceded by a progressive failure to correctly polarize sterol-rich domains after cytokinesis and are accompanied by loss of Myo1p localization. Furthermore, we found that in Sz. pombe, sterol spreading is linked to defective formation/polarization of F-actin patches and disruption of endocytosis and that these processes are aberrant in btn1Delta cells. Consistent with a role for Btn1p in polarized growth, Btn1p has an altered location at 37 degrees C and is retained in actin-dependent endomembrane structures near the cell poles or septum.


The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut.
Immunoglobulin A (IgA) is essential to maintain the symbiotic balance between gut bacterial communities and the host immune system. Here we provide evidence that the inhibitory co-receptor programmed cell death-1 (PD-1) regulates the gut microbiota through appropriate selection of IgA plasma cell repertoires. PD-1 deficiency generates an excess number of T follicular helper (T(FH)) cells with altered phenotypes, which results in dysregulated selection of IgA precursor cells in the germinal center of Peyer's patches. Consequently, the IgAs produced in PD-1-deficient mice have reduced bacteria-binding capacity, which causes alterations of microbial communities in the gut. Thus, PD-1 plays a critical role in regulation of antibody diversification required for the maintenance of intact mucosal barrier.


Biosimilar-to-Biosimilar Switching: What is the Rationale and Current Experience?
Over time, clinicians have become increasingly comfortable embracing the prescription of biosimilars-highly similar versions of innovator or reference biological agents-for their patients with inflammatory diseases. Although a switch from a reference product to a licensed biosimilar version (or vice versa) is a medical decision robustly supported by the stepwise accumulation of clinical trial evidence concerning comparable safety, immunogenicity, and efficacy between these products, a switch from one biosimilar to another biosimilar of the same reference product, or a cross-switch, is not. Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future. Yet in clinical practice, across a diverse range of patients, the option to cross-switch from one biosimilar to another can and does arise for valid reasons such as convenience or tolerability issues, or driven by third parties (e.g., payers). In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of what is known about the science underpinning a designation of biosimilar. That knowledge then needs to be integrated with what clinicians know about their patients and their disease on a case-by-case basis. This review aims to consolidate relevant emerging real-world data and other key information about biosimilar-to-biosimilar cross-switching for prescribing clinicians. In the absence of clear clinical guidelines addressing this topic at present, this review may serve to facilitate discretionary and educated treatment decision making.


Atorvastatin protects endothelium by decreasing asymmetric dimethylarginine in dyslipidemia rats.
Asymmetric Dimethylarginine (ADMA) is an inhibitor of endogenous nitric oxide synthase, which is the key synthase for nitric oxide (NO) production. Whether statins could protect endothelium by reducing ADMA concentration is unclear, and whether this effect is associated with the dose of statins usage is also needed further studied. Dyslipidemia rat model was produced by giving high-fat and high-cholesterol diet for 8 weeks. Thereafter, low-dose (5 mg/kg body weight/day) and high-dose (20 mg/kg body weight/day) atorvastatin were orally prescribed for 4 weeks. Parameters of interest including lipid profiles, inflammatory and oxidative markers, NO production and plasma levels of ADMA and ADMA concentration of myocardium were evaluated. Liver enzymes and creatinine kinase (CK) were also detected for safety concern. At baseline, all parameters were comparable between the sham and the dyslipidemia groups. At 8 weeks of dyslipidemia establishment, as compared to the sham group, body weight and lipid profiles were significantly elevated, and plasma levels of C-reactive protein (CRP), malondialdehyde (MDA) and ADMA were concomitantly increased in accompanying with NO reduction in the dyslipidemia groups. With 4 weeks of atorvastatin therapy, as compared to the control group, lipid disorders and NO production were improved, and plasma levels of CRP, MDA and ADMA were significantly decreased in the high-dose atorvastatin group. ADMA concentration of cardiac tissues was also significantly reduced in the high-dose atorvastatin group. Notably, there was a trend to similar effects which did not reach statistical significance in the low-dose atorvastatin group when compared to the control group. Liver enzyme and CK were comparable after 4 weeks of atorvastatin therapy between groups. In rats with dyslipidemia, atorvastatin therapy could reduce plasma level of ADMA and ADMA concentration in cardiac tissues, and these effects are associated with the dose of atorvastatin therapy.


Effect of interleukin-3 and granulocyte-macrophage colony-stimulating factor on growth of xenotransplanted human tumour cell lines in nude mice.
The clonal growth of cell lines from some human solid tumours can be stimulated by haematopoietic growth factors such as recombinant human (rh) interleukin-3 (IL-3) and rh granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Among these cell lines are the human colorectal adenocarcinoma cell line HTB 38 and the human small-cell lung cancer cell line HTB 119. Here we report on a series of experiments studying the influence of subcutaneously administered rhIL-3 and rhGM-CSF on the in vivo growth of HTB 38 and HTB 119 cell lines as xenografts in athymic nu/nu BALB/c mice. Beginning 1 day after transplantation of the tumour the cytokines were administered daily for 20 days as a subcutaneous bolus distant from the tumour lesion at dose levels up to 1 mg/m2/day. The cytokines caused no significant and reproducible growth modulation of the tumours in vivo.


Disparity in prenatal care among women of colour in the USA.
To describe the disparity in prenatal care among women of colour in timing of initiation of prenatal care and total number of prenatal visits. A retrospective, descriptive design. A large, urban university midwifery faculty practice. 439 healthy women at term (37-42 weeks gestation) with a vertex singleton pregnancy, and an essentially uncomplicated prenatal course. One clinic, the university facility, provided full-scope services. The other four community clinics, all outside the university in the larger metropolitan area, were designed to provide care to low-, under-, and uninsured pregnant women. Timing of initiation of prenatal care and total number of prenatal visits were examined in relation to demographic variables, including race, education, age, marital status, method of payment and clinic sites. Significant differences in initiation of prenatal care and total number of prenatal visits were documented. The non-Hispanic white women at the university hospital clinic, with high school or college degrees and insurance or Medicaid, were more likely to visit prenatal clinics. Examination of association between timing of initiation of prenatal care and demographic variables showed significant differences in race and education. This study reflects the difficulty in access to care faced by women of colour. When comparing 1997 national survey findings with those of a 2001 study, about 40% of the 50 States and the District of Columbia showed an increase in the frequency of women receiving late care or no care; additionally, a disparity in access to prenatal care between non-Hispanic white and non-white women was noted in most of these areas. The number of births to women of colour delivered by midwives has rapidly increased in recent years. Also, the numbers of babies born to women of colour is anticipated to surpass 50% in the next few decades. Considering the increased proportion of births to women of colour, special attention to promote early prenatal care for these populations is needed. Recruitment and retention efforts for non-white midwives, regular education for cultural competence of midwives, and provision of culturally and linguistically appropriate care for women of colour should be considered.


IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family.
Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.


Combined internal and external fixation of distal radius fractures.
Combined internal and external fixation of distal radius fractures is used most commonly to treat injuries with joint surface or metaphyseal comminution. External fixation aids reduction intraoperatively and facilitates arthroscopic, per-cutaneous, or open manipulation of the fracture. Internal fixation maintains precise reduction of critical anatomy, principally the contour and orientation of the articular surface. Postoperatively the fixator functions as a neutralization device, preventing fracture collapse and decreasing the biomechanical demands on the internal fixation hardware. The combined technique exploits the benefits of both forms of fixation, allowing each to be used to full advantage in the treatment of complex distal radius fractures.


Functional Group Characteristics and Pyrolysis/Combustion Performance of Karamay OS Based on FT-IR and TG-DTG Analyses.
Proximate analysis, ultimate analysis, Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetry-differential thermal analysis characterization were carried out on oily sludge (OS) samples OS1-OS5, from Karamay, Xinjiang, China. The Coast-Redfern model (CRm) was used to simulate the pyrolysis and combustion kinetics of oily samples. The results showed that the peak area percentage of benzene ring trisubstitution of OS5, in the range of 700-900 cm-1, is close to 75%, corresponding to its high volatile content. Based on the kinetic analysis by the CRm, it is found that the fitting degree of the five samples is better when the reaction order is selected as n = 2, with R 2 close to 1.00 and 2RT/E to 0. Among them, the S N and D W of OS5 are 17.8 × 10-10%2 min-2 °C-3 and 0.10899 × 10-5% min-1 °C-2, respectively, higher than those of other samples, indicating a good combustion performance.


The effects of different task repetition schedules on oral narratives of L2 learners with high and low working memory capacity.
The present study investigated the effects of different task repetition (TR) schedules on oral complexity, accuracy, and fluency (CAF) of L2 learners with high and low working memory capacity (WMC). To this end, 36 intermediate Iranian learners were assigned to two groups by means of a speaking span task: task repetition of high WMC learners (TRHWM) and task repetition of low WMC leaners (TRLWM). The learners in both groups were required to watch a silent animation, retell the story, and then repeat it immediately. They were also asked to repeat the same task after three days and a week without having a chance to watch the animation. The learners' oral task performances were recorded, coded, and analyzed in terms of the CAF measures. Results revealed that different TR schedules assisted low-WMC L2 learners with improving their complexity measure in terms of lexical diversity such that there was a statistically significant difference between the two groups from the first to the last oral performance. In addition, the findings bear pedagogical significance in that they add support to the positive effect of using different task repetition schedules on the oral performances of both high- and low-WMC L2 learners.


Estimating the prevalence of autism spectrum disorder in Lebanon.
This cross-sectional survey examines the prevalence rate of Autism spectrum disorder (ASD) in 818 children (16-48 months) across all Lebanese regions. Screening was done using the revised form of the Modified-Checklist for Autism in Toddlers. Based on the total score of items failed, children were classified into 3 categories of ASD risk (low, moderate and high). Phone calls follow-up interviews and clinical assessments for diagnosis ascertainment were conducted. Given the caregivers' reluctance to participate, the prevalence rate was estimated between 49 and 513 per 10,000 with a male predominance. Our prevalence estimation, even under restrictive assumptions, is higher than elsewhere in the Arab region. Anti- stigma interventions adapted to the socio-cultural context are needed prior to future research in the field.


Understanding of mouse and human bladder at single-cell resolution: integrated analysis of trajectory and cell-cell interactive networks based on multiple scRNA-seq datasets.
To elaborately decipher the mouse and human bladders at single-cell levels. We collected more than 50,000 cells from multiple datasets and created, up to date, the largest integrated bladder datasets. Pseudotime trajectory of urothelium and interstitial cells, as well as dynamic cell-cell interactions, was investigated. Biological activity scores and different roles of signaling pathways between certain cell clusters were also identified. The glucose score was significantly high in most urothelial cells, while the score of H3 acetylation was roughly equally distributed across all cell types. Several genes via a pseudotime pattern in mouse (Car3, Dkk2, Tnc, etc.) and human (FBLN1, S100A10, etc.) were discovered. S100A6, TMSB4X, and typical uroplakin genes seemed as shared pseudotime genes for urothelial cells in both human and mouse datasets. In combinational mouse (n = 16,688) and human (n = 22,080) bladders, we verified 1,330 and 1,449 interactive ligand-receptor pairs, respectively. The distinct incoming and outgoing signaling was significantly associated with specific cell types. Collagen was the strongest signal from fibroblasts to urothelial basal cells in mouse, while laminin pathway for urothelial basal cells to smooth muscle cells (SMCs) in human. Fibronectin 1 pathway was intensely sent by myofibroblasts, received by urothelial cells, and almost exclusively mediated by SMCs in mouse bladder. Interestingly, the cell cluster of SMCs 2 was the dominant sender and mediator for Notch signaling in the human bladder, while SMCs 1 was not. The expression of integrin superfamily (the most common communicative pairs) was depicted, and their co-expression patterns were located in certain cell types (eg, Itgb1 and Itgb4 in mouse and human basal cells). This study provides a complete interpretation of the normal bladder at single-cell levels, offering an in-depth resource and foundation for future research.


Transgenerational effects of adolescent nicotine exposure in rats: Evidence for cognitive deficits in adult female offspring.
This study investigated whether adolescent nicotine exposure in one generation of rats would impair the cognitive capacity of a subsequent generation. Male and female rats in the parental F0 generation were given twice-daily i.p. injections of either 1.0mg/kg nicotine or an equivalent volume of saline for 35days during adolescence on postnatal days 25-59 (P25-59). After reaching adulthood, male and female nicotine-exposed rats were paired for breeding as were male and female saline control rats. Only female offspring were used in this experiment. Half of the offspring of F0 nicotine-exposed breeders and half of the offspring of F0 saline control rats received twice-daily i.p. injections of 1.0mg/kg nicotine during adolescence on P25-59. The remainder of the rats received twice-daily saline injections for the same period. To evaluate transgenerational effects of nicotine exposure on complex cognitive learning abilities, F1 generation rats were trained to perform a highly structured serial pattern in a serial multiple choice (SMC) task. Beginning on P95, rats in the F1 generation were given either 4days of massed training (20patterns/day) followed by spaced training (10 patterns/day) or only spaced training. Transgenerational effects of adolescent nicotine exposure were observed as greater difficulty in learning a "violation element" of the pattern, which indicated that rats were impaired in the ability to encode and remember multiple sequential elements as compound or configural cues. The results indicated that for rats that received massed training, F1 generation rats with adolescent nicotine exposure whose F0 generation parents also experienced adolescent nicotine exposure showed poorer learning of the violation element than rats that experienced adolescent nicotine exposure only in the F1 generation. Thus, adolescent nicotine exposure in one generation of rats produced a cognitive impairment in the next generation.


The trajectories of particles suspended in electrolytes under the influence of crossed electric and magnetic fields. Possible explanation of the sensitivity of organism to magnetic fields.
We observed that particles, suspended in an electrolyte and brought into crossed magnetic and electric fields of low intensities, will deviate in the central part of the electrophoresis chamber of a standard Zeiss Cytopherometer with a component vertical to both fields. The direction and magnitude, however, were sharply at variance with what would be expected by the action of the Lorentz force (EMF) on the surface of the particles. The magnitude of the deviation depends upon the magnetic and electric field strength, the ion concentration of the suspension medium and the geometry of the chamber. The movement of the particles is due to streaming of the electrolyte which is mainly caused by inhomogeneities of the electric field in the electrophoresis chamber. The magnitude of the effect is high enough to occur physiological conditions. Magneto-electrophoretic streaming might eventually act as a transducer mechanism which could explain the ability of some animals to orientate themselves in the geomagnetic field.


Gertrude Herzfeld: The woman who dared to be a surgeon.
Gertrude Marianne Amalia Herzfeld (1890-1981), the first practicing female surgeon in Scotland, overcame bias against women in medicine and pediatric specialists in surgery. After her graduation from the University of Edinburgh Medical School (1914), she became the first female house surgeon at the Royal Hospital for Sick Children, Edinburgh. In 1920, she became the first practicing woman surgeon to become a Fellow of the Royal College of Surgeons of Edinburgh. She left a handful of publications in pediatric surgery: a "radical cure" for inguinal hernia, i.e., early surgery (1925); a review of abdominal surgery in infancy and childhood (1937); surgery for the acute abdomen (1939); and intestinal obstruction (1945). They offer a twenty-year window into how children's surgery was once practiced, when operations were done in patients' homes, and decisions for operation depended solely on the history and physical exam without laboratory testing and radiological imaging. As a series of snapshots over two decades, they reveal how her practice evolved in such areas as fluid resuscitation and radiological reduction of intussusception. She remained steadfast to a careful physical examination and early operation. While she did not document her practice in the care of children with ambiguous genitalia and intersex conditions, she approached the formidable anatomic, psychological, and social challenges of her patients and their families with patience and understanding. Herzfeld was devoted to the care of yet another marginalized population that today is subsumed by the acronym LGBTQIA, yet another area where she was far ahead of her time. Level of evidence: Level VII.


The colony stimulating factors.
Hematopoiesis is a dynamic process, which generate in the range of 10(9) cells/kg each day of erythroid and myeloid cells respectively. In vitro assays that were developed 20 years ago, have been used to define factors that can stimulate growth and differentiation of bone marrow (BM) derived progenitor cells. These growth factors for hematopoiesis were termed Colony Stimulating Factors (CSFs) since the assay system was to induce colonies. With the application of molecular biologic approaches, the genes encoding for these CSFs have been localized and cloned. Production of CSFs and other soluble signal substances (cytokines) as pure proteins have led to important insights into how hematopoiesis is regulated by a complex network made up by interactions between cells and cytokines. The availability of CSFs in clinically useful amounts has also led to clinical trials with new strategies for treating hematopoietic dysfunctions, congenital or acquired. Because others have recently reviewed clinical applications or basic science studies on the colony stimulating factors, we will summarize the two with focus on common features between the different CSFs.


Stable MSAP markers for the distinction of Vitis vinifera cv Pinot noir clones.
Grapevine is one of the most economically important fruit crops. Molecular markers have been used to study grapevine diversity. For instance, simple sequence repeats are a powerful tool for identification of grapevine cultivars, while amplified fragment length polymorphisms have shown their usefulness in intra-varietal diversity studies. Other techniques such as sequence-specific amplified polymorphism are based on the presence of mobile elements in the genome, but their detection lies upon their activity. Relevant attention has been drawn toward epigenetic sources of variation. In this study, a set of Vitis vinifera cv Pinot noir clones were analyzed using the methylation-sensitive amplified polymorphism technique with isoschizomers MspI and HpaII. Nine out of fourteen selective primer combinations were informative and generated two types of polymorphic fragments which were categorized as "stable" and "unstable." In total, 23 stable fragments were detected and they discriminated 92.5 % of the studied clones. Detected stable polymorphisms were either common to several clones, restricted to a few clones or unique to a single clone. The identification of these stable epigenetic markers will be useful in clonal diversity studies. We highlight the relevance of stable epigenetic variation in V. vinifera clones and analyze at which level these markers could be applicable for the development of forthright techniques for clonal distinction.


Formation of the active zone at developing neuromuscular junctions in larval and adult bullfrogs.
Development of the presynaptic active zone was studied at neuromuscular junctions with freeze-fracture electron microscopy in larval and adult bullfrogs. In rudimentary larval neuromuscular junctions, clusters of active zone particles were scattered over the P-face of the presynaptic membrane. Vesicle openings were observed at these terminals even though active zone particles lacked the mature pattern of two double rows. Gradually, active zone particles became organized into rows, but they were still randomly located and oriented. Once junctional folds were observed in replicas, developing active zones were located opposite to the folds, as in mature terminals. Multiple terminals occupying the same junctional gutters were also observed. At the end of metamorphosis, most active zones were still immature in appearance and had only grown to one third of their mature length. After metamorphosis, the number of active zone segments aligned at the same junctional fold increased. These discontinuous short active zones then elongated, joined together, and finally formed the mature active zones. Signs suggesting synapse elimination such as disorganization of active zones, absence of intramembrane particles in varicosities, and exposed muscle membranes with patches of acetylcholine receptor aggregates were observed. In some multiply innervated junctions, one terminal had mature active zones with vesicle openings, the other in the same gutter displayed disorganized active zones without vesicle openings, although both terminals showed similar sizes and distributions of background particles. This study suggests that developing active zones, as is the case for regenerating active zones in the adult, are functional before the mature organization is formed. The sequence of development of active zones is also similar to that of regeneration except for the random location and orientation of early active zones in tadpoles. The comparison between regeneration and development further indicates that the process of active zone formation is related to junctional folds and/or associated structures. It is also suggested that synapse elimination may involve degenerative changes in presynaptic membranes, although direct evidence remains to be provided.


[A long-time presence of a foreign body in an episiotomy scar].
The object of our study was a long-time presence of a foreign body in an episiotomy scar. A case of 46-year old woman with a palpable tumour in a perineal region is described. This false tumour was caused by a surgical needle which was left in the body of the patient 19 years ago during the episiorrhaphy after the last labour. Because of a character and localisation of the change the method of choice was surgical treatment which completely eliminated all symptoms.


Analysis of T-2 and HT-2 toxins in oats and other cereals by means of HPLC with fluorescence detection.
Bearing in mind the high toxicity of T-2 and HT-2 toxins which occur in cereals (mainly in oats) EU plans legal limits for these mycotoxins. The occurrence data are insufficient because reliable and sensitive analysis methods are not available.A sensitive HPLC gradient method was developed which is applicable with common HPLC equipment (HPLC with fluorescence detection). After extraction of the toxins from sample matrix with methanol/water the diluted extracts were cleaned-up using immunoaffinity columns and then derivatized with 1-anthroylnitrile/DMAP. The T-2 and HT-2 toxins were separated from peaks of the cereal matrix and derivatization reagent by means of a relatively complex HPLC gradient method. The method was validated for oats, wheat, rye, barley, and maize. The recovery rates were in the range of 70-99%, the precision (RSDR) of 3-8%. The limits of detection of T-2 and HT-2 toxins were 1 μg/kg. A total of 119 samples of cereals and cereal products was analyzed according to the optimized method. The analyses of 54 samples of dehulled oats and of 11 samples of processed oat products from food industry had a contamination frequency of 100%. The contents (sum of T-2 and HT-2 toxins) amounted to 3 to 174 μg/kg for the dehulled oats and to 4 to 48 μg/kg for the processed oat products. 29 samples of maize and maize products had a contamination frequency of 80% (2-106 μg/kg in the sum of T-2 and HT-2 toxins). In the samples of wheat and barley the toxins were detected only occasionally (contents: 1-10 μg/kg), in rye not at all.


Lentivirus-mediated disintegrin and metalloproteinase 17 RNA interference reversed the acquired resistance to gefitinib in lung adenocarcinoma cells in vitro.
The aim of the study is to evaluate the effects of silencing a disintegrin and metalloproteinase 17 (ADAM17) gene expression by lentivirus-mediated RNA interference (RNAi) in the gefitinib-resistant lung adenocarcinoma cells, and then to explore whether the recombinant lentivirus mediated ADAM17 RNAi reversed the acquired resistance of lung adenocarcinoma to gefitinib in vitro. The gefitinib-resistant RPC-9 cells were established and the mutations of EGFR were detected by gene sequencing. The ADAM17 shRNA expression vectors were constructed and packaged to recombinant lentivirus. The cell proliferation viability was detected by MTT, and cellular apotosis was analyzed by flow cytometry assay. The expression levels of ADAM17, EGFR and the phosphorylated EGFR were respectively detected by reverse transcription polymerase chain reaction and western blot. TGF-α production in the supernatant was detected by enzyme-linked immunosorbent assay. The gefitinib-resistant RPC-9 cells in which mutated EGFR (exon 20) carried 790T > T/M mutation were established. When the concentrations of gefitinib were less than 10μmol/L, there were no significant changes in the apoptosis and cellular proliferation of RPC-9 with the dose-escalation of gefitinib. The cell proliferation viability of RPC-9 was significantly decreased by lentivirus mediated ADAM17 RNAi (P < 0.05). Gefitinib did not inhibit ADAM17 expression in both the gefitinib-sensitive PC-9 and gefitinib-resistant RPC-9 cells (P > 0.05). Gefitinib had no significant effects on TGF alpha production in the supernatants (P > 0.05). Gefitinib did not inhibit EGFR expression in gefitinib-sensitive PC-9 and gefitinib-resistant RPC-9 cells (P > 0.05). The phosphorylation of EGFR in gefitinib-sensitive PC-9 cells was significantly inhibited by gefitinib (P < 0.05), but that in gefitinib-resistant RPC-9 could not be inhibited by gefitinib (P > 0.05). Lentivirus mediated ADAM17 RNAi significantly inhibited the mRNA and protein expression of ADAM17 in gefitinib-resistant RPC-9 cells (P < 0.05), as well as TGF alpha production in the supernatants (P < 0.05). Also, the phosphorylation of EGFR was significantly reduced in gefitinib-resistant RPC-9 cells by lentivirus mediated ADAM17 RNAi (P < 0.05); however, the mRNA and protein expression of EGFR could not be inhibited. Lentivirus mediated ADAM17 RNAi may reverse the acquired resistance of lung adenocarcinoma to gefitinib via inhibiting the upstream of EGFR signal pathway, which may provide a new therapeutic target to solve the acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:196-205, 2018.


Relationship of genotype to level of hepatitis C viraemia determined by competitive polymerase chain reaction.
To compare the levels of hepatitis C virus (HCV) viraemia in carriers of the same genotype in various stages of chronic HCV infection, we quantified the amount of HCV RNA by competitive polymerase chain reaction and determined HCV genotype using type-specific primers. The study population included 255 patients with chronic HCV infection (asymptomatic 33, chronic hepatitis 141, liver cirrhosis 50, hepatocellular carcinoma 31). Of these 255, the prevalence of HCV RNA genotype II was 67.8%, genotype III, 17.3% and genotype IV, 14.9%; no genotype I was found. The level of HCV RNA (logarithmic transformed copy numbers per 50 microliters of serum) was significantly higher in subjects of genotype II than in those of genotypes III or IV (mean titre 5.8 +/- 1.0 vs. 5.1 +/- 1.2 and 4.8 +/- 1.1, P < 0.05, respectively). There was no significant difference in the level of HCV RNA between genotypes III and IV. Of 173 patients of genotype II, there were no significant differences between the level of HCV RNA and the stage of liver disease or in the level of HCV RNA by age. Of the 129 with genotype II with a history of blood transfusion, there was no significant difference between the level of HCV RNA of patients with and without a history of transfusion or between that of patients with a history of blood transfusion and the time elapsed since blood transfusion. The level of HCV viraemia depended on the genotype of HCV RNA and did not correlate to age or to the stage of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)


A coiled-coil-based design strategy for the thermostabilization of G-protein-coupled receptors.
Structure elucidation of inactive-state GPCRs still mostly relies on X-ray crystallography. The major goal of our work was to create a new GPCR tool that would provide receptor stability and additional soluble surface for crystallization. Towards this aim, we selected the two-stranded antiparallel coiled coil as a domain fold that satisfies both criteria. A selection of antiparallel coiled coils was used for structure-guided substitution of intracellular loop 3 of the β3 adrenergic receptor. Unexpectedly, only the two GPCR variants containing thermostable coiled coils were expressed. We showed that one GPCR chimera is stable upon purification in detergent, retains ligand-binding properties, and can be crystallized. However, the quality of the crystals was not suitable for structure determination. By using two other examples, 5HTR2C and α2BAR, we demonstrate that our approach is generally suitable for the stabilization of GPCRs. To provide additional surface for promoting crystal contacts, we replaced in a structure-based approach the loop connecting the antiparallel coiled coil by T4L. We found that the engineered GPCR is even more stable than the coiled-coil variant. Negative-staining TEM revealed a homogeneous distribution of particles, indicating that coiled-coil-T4L receptor variants might also be promising candidate proteins for structure elucidation by cryo-EM. Our approach should be of interest for applications that benefit from stable GPCRs.


Predictive properties of visual adaptation.
What humans perceive depends in part on what they have previously experienced. After repeated exposure to one stimulus, adaptation takes place in the form of a negative correlation between the current percept and the last displayed stimuli. Previous work has shown that this negative dependence can extend to a few minutes in the past, but the precise extent and nature of the dependence in vision is still unknown. In two experiments based on orientation judgments, we reveal a positive dependence of a visual percept with stimuli presented remotely in the past, unexpectedly and in contrast to what is known for the recent past. Previous theories of adaptation have postulated that the visual system attempts to calibrate itself relative to an ideal norm or to the recent past. We propose instead that the remote past is used to estimate the world's statistics and that this estimate becomes the reference. According to this new framework, adaptation is predictive: the most likely forthcoming percept is the one that helps the statistics of the most recent percepts match that of the remote past.


Butterfly wing color made of pigmented liquid.
A previously undescribed mechanism underlying butterfly wing coloration patterns was discovered in two distantly related butterfly species, Siproeta stelenes and Philaethria diatonica. These butterflies have bright green wings, but the color pattern is not derived from solid pigments or nanostructures of the scales or from the color of the cuticular membrane but rather from a liquid retained in the wing membrane. Wing structure differs between the green and non-green areas. In the non-green region, the upper and lower cuticular membranes are attached to each other, whereas in the green region, we observed a space of 5-10 μm where green liquid is held and living cells are present. A pigment analysis and tracer experiment revealed that the color of the liquid is derived from hemolymph components, bilin and carotenoid pigments. This discovery broadens our understanding of the diverse ways in which butterfly wings obtain their coloration and patterns.


Urinary electrolyte excretion and orthostatic response of blood pressure and plasma renin activity in children with postural hypotension before and after treatment with Dihydergot.
Na and K metabolism, and orthostatic response of blood pressure and plasma renin activity (PRA) were studied in six children, aged 10 to 15 years, with postural hypotension before and after treatment with Dihydergot (DHE). All abnormal findings which we had already observed in children with postural hypotension (i.e. low fractional excretion of filtered Na in spite of low PRA, extremely high PRA on fainting, great postural fall in blood pressure, and so on) improved on treatment with DHE. This suggests that these abnormal physiological findings found in children with postural hypotension may result from increased venous pooling which can be reduced by DHE. Consequently, DHE seems an excellent drug to treat postural hypotension from the physiological point of view.


Electrical coupling between primary hair cells in the statocyst of the squid, Alloteuthis subulata.
Intracellular recordings were made from primary sensory hair cells located on the dorsal side of the anterior crista segment of the squid statocyst. These hair cells were electrophysiologically identified by the occurrence of an antidromic action potential after electrical stimulation of the crista nerve. Two types of subthreshold, depolarising potentials were observed in the primary sensory hair cells. Firstly, those due to efferent inputs onto the primary hair cells and secondly those correlated one-to-one with action potentials in neighbouring primary hair cells. The former depolarising potentials could be blocked by bath applied cobalt, indicating chemical transmission, while the latter could not. Injection of a depolarising or hyperpolarising current into a primary hair cell depolarised or hyperpolarised, respectively, a neighbouring primary hair cell implying that the hair cells are electrically coupled with an electrical coupling coefficient of up to 0.4.


Safety and Effectiveness of Maternal COVID-19 Vaccines Among Pregnant People and Infants.
Evidence has consistently demonstrated that COVID-19 messenger RNA (mRNA) vaccines are safe when given during pregnancy. COVID-19 mRNA vaccines protect pregnant people and their infants who are too young to receive COVID-19 vaccines. Although generally protective, monovalent vaccine effectiveness was lower during SARS-CoV-2 Omicron variant predominance, in part due to changes in the Omicron spike protein. Bivalent vaccines, that combine ancestral strain and Omicron variant, may improve protection against Omicron variants. Everyone, including pregnant people, should stay up to date with recommended COVID-19 vaccines and bivalent booster, when eligible.


Residues in common flicker and mountain bluebird eggs one year after a DDT application.
Common flicker (Colaptes auratus) and mountain bluebird (Sialia currucoides) eggs were examined 1 year after DDT application and showed a marked difference. Residue levels in mountain bluebird eggs were approximately 10 times higher than in common flicker eggs (5.29 to 0.58 ppm wet weight). These differences can be explained by disparate dietary habits. The mean level in American kestrel (Falco sparverius) eggs collected in the spray area at the same time was 6.42 ppm wet weight.


Photosynthetic gas exchange response of poplars to steady-state and dynamic light environments.
The steady-state and dynamic photosynthetic response of two poplar species (Populus tremuloides and P. fremontii) to variations in photon flux density (PFD) were observed with a field portable gas exchange system. These poplars were shown to be very shade intolerant with high light saturation (800 to 1300 μmol photons m-2 s-1) and light compensation (70 to 100 μmol m-2 s-1) points. Understory poplar leaves showed no physiological acclimation to understory light environments. These plants become photosynthetically induced quickly (10 min). Activation of Rubisco was the primary limitation for induction, with stomatal opening playing only a minor role. Leaves maintained high stomatal conductances and stomata were unresponsive to variations in PFD. Leaves were very efficient at utilizing rapidly fluctuating light environments similar to those naturally occurring in canopies. Post-illumination CO2 fixation contributed proportionally more to the carbon gain of leaves during short frequent lightflecks than longer less frequent ones. The benefits of a more dynamic understory light environment for the carbon economy of these species are discussed.