Evaluating adolescents in juvenile detention facilities for urogenital chlamydial infection: costs and effectiveness of alternative interventions.
Adolescents in juvenile detention facilities present a unique opportunity to diagnose and treat sexually transmitted diseases. To evaluate the effectiveness and costs of different strategies for the diagnosis and treatment of chlamydial infection in adolescents in juvenile detention.Design, Setting, and Subjects For a cohort of adolescents in a juvenile detention facility, sex-specific decision models were developed comparing strategies for diagnosing and treating chlamydial infection. These strategies included not screening, treating everyone, and testing (with leukocyte esterase [LE], ligase chain reaction [LCR], or history and symptoms) followed by treatment for those with positive test results. Two different time horizons were considered: immediate and extended. In the immediate time horizon, we performed a cost-effectiveness analysis looking only at the outcomes associated with treating current infections; in the extended time horizon, we performed a cost-minimization analysis comparing the estimated total costs of diagnosing and treating Chlamydia as well as those associated with complications occurring up to 20 years in the future. In males, the immediate-time-horizon evaluation revealed that treating on the basis of urine LE results produced the lowest incremental cost-effectiveness ratio ($80 per infection treated). In the extended-time-horizon cost-minimization analysis, treating males on the basis of urine LE results was again found to be the least expensive strategy ($10.11 per person). Two other strategies, confirming urine LE results with LCR ($10.96 per person) and screening with urine LCR ($14.04 per person), were found to be less expensive than not screening ($16.66 per person). In females, the immediate-time-horizon evaluation found that treating on the basis of symptoms and history resulted in treating about half the cases of chlamydial infection and produced the lowest incremental cost-effectiveness ratio ($74 per infection treated). More infections were treated when treatment was based on urine LCR results with only a small increase in the incremental cost per case treated ($95 per infection treated). In the extended-time-horizon cost-minimization analysis, treating all females empirically and treating based on results of urine LCR testing were the least expensive strategies ($18.81 and $18.98 per person, respectively). The results were sensitive to several variables, including prevalence of chlamydial infection, in both males and females. For adolescent males in juvenile detention facilities, screening with urine LE minimizes the costs associated with diagnosis, treatment, and sequelae of urogenital chlamydial infection. For adolescent females in juvenile detention, empiric treatment and that based on urine LCR test results are the optimal strategies for managing urogenital chlamydial infection.


[Choice of influenza vaccine in people over 65 years old. Analysis of reports from international vaccination advisory committees].
Annual recommendations on influenza vaccine use in different countries are developed by influenza-specific working groups within their Immunization Advisory Committees. Adults aged 65 years and over are included in the groups for which vaccination against influenza is particularly recommended due to the morbidity associated. A variety of influenza vaccines are available, some of which boosted immunity, are licensed for use only in this specific age group, where the immune response to traditional influenza vaccines may be suboptimal. We analyze the main annual recommendations on the use of the influenza vaccine issued by advisory committees on immunization for the population over 65 years of age. The latest influenza vaccination guidelines have been selected and the recommendations for people over 65 years of age published by the main vaccination advisory committees have been reviewed. The UK Advisory Committee (JCVI) recommends the use of Quadruvalent Inactivated Influenza Vaccine with Adjuvant (aQIV) or High Dose Quadrivalent Inactivated Influenza Vaccine (QIV-HD). The US committee (ACIP) does not express a preference for any type of vaccine. The Australian committee (ATAGI) preferably recommends adjuvanted influenza vaccine. The advisory committees of Canada and Germany (NACI, STIKO) and the European Center for Disease Control (Ecdc) recommend using any of the age-appropriate flu vaccines available, although they bet on the The UK Advisory Committee (JCVI) recommends the use of Quadruvalent Inactivated Influenza Vaccine with Adjuvant (aQIV) or High Dose Quadrivalent Inactivated Influenza Vaccine (QIV-HD). The US committee (ACIP) does not express a preference for any type of vaccine. The Australian committee (ATAGI) preferably recommends adjuvanted influenza vaccine. The advisory committees of Canada and Germany (NACI, STIKO) and the European Center for Disease Control (Ecdc) recommend using any of the age-appropriate flu vaccines available, although they bet on the use of inactivated quadrivalent flu vaccine high dose at the individual level for those over 65 years.use of inactivated quadrivalent flu vaccine high dose at the individual level for those over 65 years. It is necessary further studies and improvement in their quality that analyze the different vaccines available and their comparability, although the use of reinforced immunity vaccines is generally recommended in the population over 65 years of age.


Gene expression analysis predicts insect venom anaphylaxis in indolent systemic mastocytosis.
Anaphylaxis to insect venom (Hymenoptera) is most severe in patients with mastocytosis and may even lead to death. However, not all patients with mastocytosis suffer from anaphylaxis. The aim of the study was to analyze differences in gene expression between patients with indolent systemic mastocytosis (ISM) and a history of insect venom anaphylaxis (IVA) compared to those patients without a history of anaphylaxis, and to determine the predictive use of gene expression profiling. Whole-genome gene expression analysis was performed in peripheral blood cells. Twenty-two adults with ISM were included: 12 with a history of IVA and 10 without a history of anaphylaxis of any kind. Significant differences in single gene expression corrected for multiple testing were found for 104 transcripts (P < 0.05). Gene ontology analysis revealed that the differentially expressed genes were involved in pathways responsible for the development of cancer and focal and cell adhesion suggesting that the expression of genes related to the differentiation state of cells is higher in patients with a history of anaphylaxis. Based on the gene expression profiles, a naïve Bayes prediction model was built identifying patients with IVA. In ISM, gene expression profiles are different between patients with a history of IVA and those without. These findings might reflect a more pronounced mast cells dysfunction in patients without a history of anaphylaxis. Gene expression profiling might be a useful tool to predict the risk of anaphylaxis on insect venom in patients with ISM. Prospective studies are needed to substantiate any conclusions.


Separating the effects of age and walking speed on gait variability.
Gait variability has been correlated with fall risk in the elderly. Older adults typically display greater variability than young adults, but the cause of this increase is unclear. Slower walking leads to greater variability in young adults, but slow speeds are also typical in older adults. Increased variability in older adults may result from slower walking speeds, or possibly from other factors related to aging. We tested whether greater variability in healthy older adults could be attributed directly to slower walking speed. Eighteen healthy older adults (age 72+/-6) and 17 gender-, height- and weight-matched young adults (age 23+/-3) walked on a treadmill at speeds of 80-120% of their preferred speed. Variability of spatio-temporal gait measures, lower extremity joint angles, and trunk motions were quantified, along with bilateral isometric leg strengths and passive joint ranges of motion. Preferred walking speeds were not different between our healthy elderly and young subjects. In both groups, variability was speed-dependent for stride time, frontal hip and knee motions, knee internal/external rotations, and all trunk motions (p<0.002). Older adults exhibited greater variability (p=0.0003) for trunk roll, independent of changes in speed. Step length (p=0.005), stride time (p=0.018), and trunk pitch (p=0.022) exhibited similar trends. This greater variability was explained by decreased leg strength and passive ranges of motion. Thus, the greater variability observed in the gait of older adults may result more from loss of strength and flexibility than from their slower speeds.


Facial follicular cysts: a case of lichen planus follicularis tumidus?
Lichen planus follicularis tumidus (LPFT) represents an uncommon variety of lichen planus (LP). Clinically, it presents with prominent purplish lesions or white-pigmented yellowish cysts and comedones. Histopathologically, it is similar to lichen planopilaris, and it is additionally characterized by follicles and cysts surrounded by a lichenoid lymphocytic infiltrate. The most common location is the retroauricular region, and it may be associated with other variants of LP. Herein, we describe the case of a 50-year-old woman with a history of lower limb hypertrophic LP who subsequently presented with multiple pink, tumid, pruritic plaques with white-yellow cysts and comedones extensively affecting the bilateral face. Histopathologic examination revealed a lichenoid infiltrate surrounding the follicles and cysts. We diagnosed LPFT and began treatment with topical corticosteroids, antihistamines, systemic corticosteroids and oral acitretin without improvement. Subsequently, the patient had an acceptable response to cyclosporine at doses of 5 mg/kg/day with remission of itching and tumidity but with residual cysts and comedones remaining. To date, the literature contains only 16 cases of LPFT. To our knowledge, this is the most severe case and is the only one with cessation of disease activity in response to cyclosporine.


Heterochromatic stray light in UV absorption spectrometry: a new test method.
A new method of estimating the amount of heterochromatic stray light in UV spectrophotometers is described. The method uses the same solution filters with sharp UV absorption edges as ASTM Test Method E387, but one measures the apparent absorbance of a 10-mm path-length cell in the sample beam relative to a 5-mm cell in the reference beam. Scanning toward shorter wavelengths, one records an apparent absorbance maximum which is a direct measure of the stray light. This method was found to be in satisfactory agreement with the ASTM method in comparative tests of several spectrophotometers at different wavelengths between 200 and 390 nm, using KC1, KI, Nal, acetone, and NaNO(2) solution filters. The new method proved to be simpler, the main advantage being that the apparent absorbance maximum occurs at considerably lower scale values than the corresponding absorbance plateau measured by the ASTM method. This reduces the need for successive attenuations of the reference beam every time the spectrophotometer runs off scale. In many instances the new method required no attenuation at all.


Cerebral specialization in young adults with Down syndrome.
Adults with and without Down syndrome performed a rapid unimanual finger-tapping task alone and while sound-shadowing high frequency words. For male subjects, the concurrent speech disrupted right-hand, but not left-hand performance. Females suffered finger-tapping decrements in both hands in the dual-task situation. These results provide no evidence for reverse (right hemisphere) lateralization of speech in individuals with Down syndrome.


Continuous(ly) missing outcome data in network meta-analysis: A one-stage pattern-mixture model approach.
Appropriate handling of aggregate missing outcome data is necessary to minimise bias in the conclusions of systematic reviews. The two-stage pattern-mixture model has been already proposed to address aggregate missing continuous outcome data. While this approach is more proper compared with the exclusion of missing continuous outcome data and simple imputation methods, it does not offer flexible modelling of missing continuous outcome data to investigate their implications on the conclusions thoroughly. Therefore, we propose a one-stage pattern-mixture model approach under the Bayesian framework to address missing continuous outcome data in a network of interventions and gain knowledge about the missingness process in different trials and interventions. We extend the hierarchical network meta-analysis model for one aggregate continuous outcome to incorporate a missingness parameter that measures the departure from the missing at random assumption. We consider various effect size estimates for continuous data, and two informative missingness parameters, the informative missingness difference of means and the informative missingness ratio of means. We incorporate our prior belief about the missingness parameters while allowing for several possibilities of prior structures to account for the fact that the missingness process may differ in the network. The method is exemplified in two networks from published reviews comprising a different amount of missing continuous outcome data.


Global increase in quaternary explosive volcanism.
The worldwide distribution of volcanic ash has been determinmined from 320 deep-sea sections drilled during the Deep Sea Drilling Project. The ash distribution in the deep-sea sections, which span the last 20 million years, indicates that there has been a much higher rate of explosive volcanism from both island arc and hot spot volcanoes during the last 2 million years. This episode, and perhaps another in the Middle Miocene cprrelates with previously reported widespread synchronism in increased volcanicity in certain oceanic islands. Increased Quaternary volcanism coincides approximately with that episode of the Cenozoic marked by major and rapidly fluctuating climatic change.


Ion selectivity of temperature-induced and electric field induced pores in dipalmitoylphosphatidylcholine vesicles.
Temperature and electric field are known to alter the permeability of the bilayer membrane in phospholipid vesicles. A study of cation selectivity of these membrane pores is reported for multilamellar liposomes (MLV) and unilamellar large vesicles (ULV, 95 +/- 5 nm diameter) of dipalmitoylphosphatidylcholine (DPPC). The permeability of ULV to Rb+ was 1.0 X 10(-6) micrograms/s at 22 degrees C and increased to 1.1 X 10(-5) micrograms/s at the gel to liquid-crystalline transition temperature (Tm) of the bilayer, at 42 degrees C. The permeability of ULV to Rb+ continued to increase beyond the Tm and reached 1.0 X 10(-4) micrograms/s at 56 degrees C, a 100-fold increase over the permeability at 22 degrees C. In contrast, the permeability of ULV to Na+ showed a local maximum of 6.0 X 10(-6) micrograms/s at 42 degrees C and decreased at temperatures higher or lower than the Tm. For MLV, the permeability to both Rb+ and Na+ peaked dramatically at the phase transition temperature, 42 degrees C, and subsided at lower and higher temperatures. When ULV were exposed to an electric field, the permeability to Rb+, Na+, and sucrose surged at a field strength of 30 kV/cm; 30 kV/cm can induce a transmembrane potential of 210 mV. In ULV, the electrically perforated lipid bilayer exhibited selectivity for Rb+ over Na+ only at a narrow electric field range, between 31 and 33 kV/cm. For MLV, no well-defined breakdown voltage was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)


Natural APOBEC3C variants can elicit differential HIV-1 restriction activity.
The APOBEC3 (A3) family of DNA cytosine deaminases provides an innate barrier to infection by retroviruses including HIV-1. A total of five enzymes, A3C, A3D, A3F, A3G and A3H, are degraded by the viral accessory protein Vif and expressed at high levels in CD4+ T cells, the primary reservoir for HIV-1 replication in vivo. Apart from A3C, all of these enzymes mediate restriction of Vif-deficient HIV-1. However, a rare variant of human A3C (Ile188) was shown recently to restrict Vif-deficient HIV-1 in a 293T-based single cycle infection system. The potential activity of this naturally occurring A3C variant has yet to be characterized in a T cell-based spreading infection system. Here we employ a combination of Cas9/gRNA disruption and transient and stable protein expression to assess the roles of major Ser188 and minor Ile188 A3C variants in HIV-1 restriction in T cell lines. Cas9-mediated mutation of endogenous A3C in the non-permissive CEM2n T cell line did not alter HIV-1 replication kinetics, and complementation with A3C-Ser188 or A3C-Ile188 was similarly aphenotypic. Stable expression of A3C-Ser188 in the permissive T cell line SupT11 also had little effect. However, stable expression of A3C-Ile188 in SupT11 cells inhibited Vif-deficient virus replication and inflicted G-to-A mutations. A3C-Ile188 is capable of inhibiting Vif-deficient HIV-1 replication in T cells. Although A3C is eclipsed by the dominant anti-viral activities of other A3s in non-permissive T cell lines and primary T lymphocytes, this enzyme may still be able to contribute to HIV-1 diversification in vivo. Our results highlight the functional redundancy in the human A3 family with regards to HIV-1 restriction and the need to consider naturally occurring variants.


Effects of Different Local Anaesthetics on Oto-acoustic Emission Tests after Spinal Anaesthesia.
To evaluate whether there is any effect of different local anaesthetic agents on hearing loss after spinal anaesthesia. Thirty American Society of Anesthesiologists (ASA) I patients without a hearing problem were included in the study. Transient evoked oto-acoustic emissions (TEOAE) were examined. Patients were randomly separated into two groups: Group L, 15 mg isobaric levobupivacaine application and Group B, 15 mg isobaric bupivacaine application, for spinal anaesthesia. Oto-acoustic emission measurements were repeated on patients at the 24th hour after spinal anaesthesia application. No significant difference was found in the output values of the right and left ears according to the input values in group L at no kHz (p > 0.05). No significant difference was found in the output values of the right and left ears according to the input values in any kHz of Group B (p > 0.05). Fifteen milligrammes of isobaric bupivacaine and levobupivacaine had no significant difference on the effect of hearing loss after spinal anaesthesia. Hearing loss after spinal anaesthesia has many unknown issues, and deserves to be explored by performing many studies.


Current and projected burden of heart failure in the Australian adult population: a substantive but still ill-defined major health issue.
Comprehensive epidemiological data to describe the burden of heart failure (HF) in Australia remain lacking despite its importance as a major health issue. Herewith, we estimate the current and future burden of HF in Australia using best available data. Australian-specific and the most congruent international epidemiological and health utilisation data were applied to the Australian population (adults aged ≥ 45 years, 8.9 of 22.7 million total population in 2014) on an age and sex-specific basis. We estimated the current incident and prevalent cases of clinically overt/symptomatic HF (predominately those with reduced ejection fraction), hospital activity (diagnosis of HF as a primary or secondary reason for admission) and health care costs in 2014 and future prevalence and burden of HF projected to 2030. We estimated that over 61,000 (6.9 per 1000 person-years) adult Australians aged ≥ 45 years (58 % women) are diagnosed with HF with clinically overt signs and symptoms every year. On a conservative basis, 480,000 (6.3 %, 95 % CI 2.6 to 10.0 %) Australians (66 % men) are now affected by the syndrome with > 150,000 hospitalisations in excess of 1 million days in hospital per annum. The annual cost of managing HF in the community is approximately $900 million and nearly $2.7 billion ($1.5 versus $1.2 billion, men versus women) when considering the additional cost of in-patient care. We predict that the prevalence and future burden of HF will continue to increase over the next 10-15 years to nearly 750,000 people with an estimated annual health care cost of $3.8 billion. Australia is not immune to the growing magnitude and implications of a sustained epidemic of HF in an ageing population. However, its public health and economic burden will remain ill-defined until more definitive Australian-specific data are generated.


Integrin αvβ1 facilitates ACE2-mediated entry of SARS-CoV-2.
Integrins have been suggested to be involved in SARS-CoV-2 infection, but the underlying mechanisms remain largely unclear. This study aimed to investigate how integrins facilitate the ACE2-mediated cellular entry of SARS-CoV-2. We first tested the susceptibility of a panel of human cell lines to SARS-CoV-2 infection using the spike protein pseudotyped virus assay and examined the expression levels of integrins in these cell lines by qPCR, western blot and flow cytometry. We found that integrin αvβ1 was highly enriched in the SARS-CoV-2 susceptible cell lines. Additional studies demonstrated that RGD (403-405)→AAA mutant was defective in binding to integrin αvβ1 compared to its wild type counterpart, and anti-αvβ1 integrin antibodies significantly inhibited the entry of SARS-CoV-2 into the cells. Further studies using mouse NIH3T3 cells expressing human ACE2, integrin αv, integrin β1, and/or integrin αvβ1 suggest that integrin αvβ1 was unable to function as an independent receptor but could significantly facilitate the cellular entry of SASR-CoV-2. Finally, we observed that the Omicron exhibited a significant increase in the ACE2-mediated viral entry. Our findings may enhance our understanding of the pathogenesis of SARS-CoV-2 infection and offer potential therapeutic target for COVID-19.


Exposure to mutagenic disinfection byproducts leads to increase of antibiotic resistance in Pseudomonas aeruginosa.
Bacterial antibiotic resistance (BAR) in drinking water has become a global issue because of its risks on the public health. Usually, the antibiotic concentrations in drinking water are too low to select antibiotic resistant strains effectively, suggesting that factors other than antibiotics would contribute to the emergence of BAR. In the current study, the impacts of mutagenic disinfection byproducts (DBPs) on BAR were explored, using four typical DBPs: dibromoacetic acid, dichloroacetonitrile, potassium bromate, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). After exposure to DBPs, resistances to 10 individual antibiotics and multiple antibiotics were both raised by various levels, norfloxacin and polymycin B resistances were enhanced even greater than 10-fold compared with control. MX increased the resistance most observably in the selected DBPs, which was consistent with its mutagenic activity. The resistant mutants showed hereditary stability during 5-day culturing. The increase of BAR was caused by the mutagenic activities of DBPs, since mutation frequency declined by adding ROS scavenger. Mutagenesis was further confirmed by sequencing of the related genes. Our study indicated that mutagenic activities of the selected DBPs could induce antibiotic resistance, even multidrug resistance, which may partially explain the lack of agreement between BAR and antibiotic levels in drinking water.


Computers in family medicine. Automating outpatient medical practice.
The American Academy of Family Practice has been on a 4-year quest for a universal family practice office computer that it can recommend to its membership. Much as individual physicians struggle for computer "literacy," all medical organizations likewise face their own steep learning curve in the attempt to discern their memberships' needs and to provide guidance in meeting them.


Case Report of a Complex Chest Wall Reconstruction with a Cadaveric Achilles Tendon.
BACKGROUND Chest wall reconstruction is sometimes needed after resection of a thoracic malignancy. Various materials and techniques have been utilized to restore stability and integrity to the chest wall. We report what we believe is the first use of a cadaveric Achilles tendon to restore stability and function to the chest wall of a young woman who underwent chest wall resection and right upper lobectomy for a superior sulcus tumor. CASE REPORT A 46-year-old woman underwent resection of her first through fourth right ribs in addition to her right upper lobe for a squamous cell superior sulcus tumor. Because it was felt her right scapula provided sufficient coverage of her resultant chest wall defect, her chest wall was not reconstructed post-operatively. The patient experienced 2 episodes of scapular prolapse into her thoracic cavity several months after her resection. After the second episode, her right chest wall was successfully reconstructed with a cadaveric Achilles tendon to prevent further episodes of prolapse. CONCLUSIONS We believe this is the first description of chest wall reconstruction with a cadaveric Achilles tendon. The use of a cadaveric Achilles tendon should be considered for reconstruction of the chest wall after complex resection due to its strength characteristics, resistance to subsequent infection, and availability.


Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest.
Colonization of trunk neural crest derivatives in avians follows a ventral to dorsal order beginning with sympathetic ganglia, Schwann cells, sensory ganglia and finally melanocytes. Continuous crest emigration underlies this process, which is accounted for by a progressive ventral to dorsal relocation of neural tube progenitors prior to departure. This causes a gradual narrowing of FoxD3, Sox9 and Snail2 expression domains in the dorsal tube that characterize the neural progenitors of the crest and these genes are no longer transcribed by the time melanoblasts begin emigrating. Consistently, the final localization of crest cells can be predicted from their relative ventrodorsal position within the premigratory domain or by their time of delamination. Thus, a dynamic spatiotemporal fate map of crest derivatives exists in the dorsal tube at flank levels of the axis with its midline region acting as a sink for the ordered ingression and departure of progenitors. Furthermore, discrete lineage analysis of the dorsal midline at progressive stages generated progeny in single rather than multiple derivatives, revealing early fate restrictions. Compatible with this notion, when early emigrating ;neural' progenitors were diverted into the lateral ;melanocytic' pathway, they still adopted neural traits, suggesting that initial fate acquisition is independent of the migratory environment and that the potential of crest cells prior to emigration is limited.


Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding.
DRP-1 is a pro-apoptotic Ca2+/calmodulin (CaM)-regulated serine/threonine kinase, recently isolated as a novel member of the DAP-kinase family of proteins. It contains a short extra-catalytic tail required for homodimerization. Here we identify a novel regulatory mechanism that controls its pro-apoptotic functions. It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain. A negative charge at this site reduces both the binding to CaM and the formation of DRP-1 homodimers. Conversely, the dephosphorylation of Ser308, which takes place in response to activated Fas or tumour necrosis factor-alpha death receptors, increases the formation of DRP-1 dimers, facilitates the binding to CaM and activates the pro-apoptotic effects of the protein. Thus, the process of enzyme activation is controlled by two unlocking steps that must work in concert, i.e. dephosphorylation, which probably weakens the electrostatic interactions between the CaM regulatory domain and the catalytic cleft, and homodimerization. This mechanism of negative autophosphorylation provides a safety barrier that restrains the killing effects of DRP-1, and a target for efficient activation of the kinase by various apoptotic stimuli.


Nasal bone shape is under complex epistatic genetic control in mouse interspecific recombinant congenic strains.
Genetic determinism of cranial morphology in the mouse is still largely unknown, despite the localization of putative QTLs and the identification of genes associated with Mendelian skull malformations. To approach the dissection of this multigenic control, we have used a set of interspecific recombinant congenic strains (IRCS) produced between C57BL/6 and mice of the distant species Mus spretus (SEG/Pas). Each strain has inherited 1.3% of its genome from SEG/Pas under the form of few, small-sized, chromosomal segments. The shape of the nasal bone was studied using outline analysis combined with Fourier descriptors, and differential features were identified between IRCS BcG-66H and C57BL/6. An F2 cross between BcG-66H and C57BL/6 revealed that, out of the three SEG/Pas-derived chromosomal regions present in BcG-66H, two were involved. Segments on chromosomes 1 (∼32 Mb) and 18 (∼13 Mb) showed additive effect on nasal bone shape. The three chromosomal regions present in BcG-66H were isolated in congenic strains to study their individual effect. Epistatic interactions were assessed in bicongenic strains. Our results show that, besides a strong individual effect, the QTL on chromosome 1 interacts with genes on chromosomes 13 and 18. This study demonstrates that nasal bone shape is under complex genetic control but can be efficiently dissected in the mouse using appropriate genetic tools and shape descriptors.


Uncovered primary seizure foci in Lennox-Gastaut syndrome after corpus callosotomy.
Corpus callosotomy (CC) is a palliative surgical procedure to control atonic, tonic, or generalized tonic-clonic seizure in Lennox-Gastaut syndrome (LGS). Here, we report patients with LGS who underwent resective surgery, following CC better delineating the presumed seizure foci localized in one hemisphere. We retrospectively reviewed seven patients with LGS who underwent CC and subsequent cortical resection. The median follow-up duration after lobectomy was 20 months (range, 15-54 months) and three patients had follow-up periods over 24 months. The findings of video electroencephalography (EEG) monitoring, structural and functional neuroimagings were compared between pre- and post-CC. Four patients had Engel class I and one patient had Engel class II outcomes following cortical resection; post-CC, compared to pre-CC, showed better localized ictal/interictal epileptiform discharges in the unilateral frontal area in two patients, in the unilateral parieto-temporo-occipital areas in one patient and in the unilateral fronto-temporal areas in the remaining two patients. Two patients had Engel Class III outcome following cortical resection; post-CC EEG continued to show multifocal epileptiform discharges but predominantly arising from a unilateral frontal area. Following CC, positron emission tomography showed localized glucose hypometabolism of which location was concordant with post-CC EEG abnormalities in all patient. Similarly, ictal/interictal single photon emission computed tomography also showed localized abnormalities concordant with post-CC EEG abnormalities in five of the six patients. Pathological assessment revealed cortical dysplasia in six patients, whereas no pathological abnormality was found in the remaining patient, who obtained Engel Class I outcome following cortical resection. CC could change EEG findings, glucose metabolisms and cerebral blood flows, and it is sometimes helpful in delineating the primary seizure focus in patients with LGS.


The evidence of mother to child transmission of hepatitis B virus infection in Pakistan and the need for hepatitis B immunization policy change.
To establish the hepatitis B surface antigen and hepatitis B 'e' antigen seroprevalence of mothers and their children aged 6-36 months and to assess the risk of hepatitis B transmission occurring in infants born to hepatitis B surface antigen positive mothers in Pakistan. Mothers and their children were selected from eight districts of three provinces that have been identified as high hepatitis B prevalence areas between May 2010 to February 2011. Ages of the children and their vaccination status were obtained from the lady health workers' registers and also verified from the mothers. Five ml of blood was drawn from all the children and their mothers for testing. All sera were tested for anti-hepatitis B. Those found negative were run for HBsAg the sueface antigen and those positive for it were further run for hepatitis B 'e' antigen All tests were run on Abbott machine using chemiluminesence method. EPI-info 12 was used for statistical purposes. A total of 1561 mothers and their 1612 children were tested. Among the mothers, 590 (37.8%) were hepatitis B antibody positive. Remaining 971 (62.2%) samples were tested for surface antigen and 123 (12.7%) were found positive of which 27 (22%) showed HBeAg positivity. Out of 1612 children tested, 975 (60.5%) were positive. Remaining 637 (39.5%) were tested for surface antigen and 49 (8%) were found positive of which 24 (49%) were HBeAg positive with a perinatal hepatitis B virus transmission rate of 5.4% by 12 months of age. Of the 123 surface antigen positive mothers, 18 (14.6%) had children who were also positive, while of the 1489 children born to the 1438 surface antigen negative mothers, 31 (2.1%) were positive. Children born to surface antigen positive mothers had eight times higher risk of getting hepatitis B virus infection and the risk rose to 17 times if the mother was also HBeAg positive. Hepatitis B vaccination record showed that 1229 (76.25%) children were vaccinated at six weeks with pentavalent vaccine, but despite vaccination 33 (2.6%) became surface antigen positive. No vaccination was received by 320 (19.9%) children and out of these 16 (5%) became surface antigen positive. Moreover, the vaccinated and unvaccinated children born to surface antigen positive mothers were nine and 11 times respectively more likely to be exposed to the risk of hepatitis B virus transmission relative to vaccinated children born to surface antigen negative mothers. Hepatitis B vaccination given at 6, 10 and 14 weeks of birth is not sufficiently protective, indicating a strong need for the introduction of birth dose into the national immunisation system.


Lessons that patient-centered medical homes can learn from the mistakes of HMOs.
Patient-centered medical homes (PCMHs) have been endorsed by primary and specialty care medical associations, payers, and patient groups as an innovative structure for transforming health care delivery. The cornerstone principle of the PCMH is the primary care physician's coordination of a patient's use of health care services, including visits to specialists, to improve effectiveness and efficiency. This principle aligns with the vision behind the creation of HMOs, managed care organizations that were once embraced by physicians, patients, and policy analysts but have since lost much of their luster. Many patients and physicians rejected HMOs as too restrictive, objecting particularly to the concept of gatekeeping. This article reviews the HMO experience and identifies lessons applicable to PCMHs that build on the strengths of HMOs while avoiding their mistakes.


Physiological and biochemical defects in carboxyl-terminal mutants of mitochondrial DNA helicase.
Mitochondrial DNA helicase, also called Twinkle, is essential for mtDNA maintenance. Its helicase domain shares high homology with helicases from superfamily 4. Structural analyses of helicases from this family indicate that carboxyl-terminal residues contribute to NTP hydrolysis required for translocation and DNA unwinding, yet genetic and biochemical information is very limited. Here, we evaluate the effects of overexpression in Drosophila cell culture of variants carrying a series of deletion and alanine substitution mutations in the carboxyl terminus and identify critical residues between amino acids 572 and 596 of the 613 amino acid polypeptide that are essential for mitochondrial DNA helicase function in vivo. Likewise, amino acid substitution mutants K574A, R576A, Y577A, F588A, and F595A show dose-dependent dominant-negative phenotypes. Arg-576 and Phe-588 are analogous to the arginine finger and base stack of other helicases, including the bacteriophage T7 gene 4 protein and bacterial DnaB helicase, respectively. We show here that representative human recombinant proteins that are analogous to the alanine substitution mutants exhibit defects in nucleotide hydrolysis. Our findings may be applicable to understand the role of the carboxyl-terminal region in superfamily 4 DNA helicases in general.


Induction of Rod-Shaped Structures by Herpes Simplex Virus Glycoprotein I.
The envelope glycoprotein I (gI) of herpes simplex virus 1 (HSV-1) is a critical mediator of virus-induced cell-to-cell spread and cell-cell fusion. Here, we report a previously unrecognized property of this molecule. In transfected cells, the HSV-1 gI was discovered to induce rod-shaped structures that were uniform in width but variable in length. Moreover, the gI within these structures was conformationally different from the typical form of gI, as a previously used monoclonal antibody mAb3104 and a newly made peptide antibody to the gI extracellular domain (ECD) (amino acids [aa] 110 to 202) both failed to stain the long rod-shaped structures, suggesting the formation of a higher-order form. Consistent with this observation, we found that gI could self-interact and that the rod-shaped structures failed to recognize glycoprotein E, the well-known binding partner of gI. Further analyses by deletion mutagenesis and construction of chimeric mutants between gI and gD revealed that the gI ECD is the critical determinant, whereas the transmembrane domain served merely as an anchor. The critical amino acids were subsequently mapped to proline residues 184 and 188 within a conserved PXXXP motif. Reverse genetics analyses showed that the ability to induce a rod-shaped structure was not required for viral replication and spread in cell culture but rather correlated positively with the capability of the virus to induce cell fusion in the UL24syn background. Together, this work discovered a novel feature of HSV-1 gI that may have important implications in understanding gI function in viral spread and pathogenesis.IMPORTANCE The HSV-1 gI is required for viral cell-to-cell spread within the host, but the molecular mechanisms of how gI exactly works have remained poorly understood. Here, we report a novel property of this molecule, namely, induction of rod-shaped structures, which appeared to represent a higher-order form of gI. We further mapped the critical residues and showed that the ability of gI to induce rod-shaped structures correlated well with the capability of HSV-1 to induce cell fusion in the UL24syn background, suggesting that the two events may have an intrinsic link. Our results shed light on the biological properties of HSV-1 gI and may have important implications in understanding viral pathogenesis.


Ternary copper complexes and manganese (III) tetrakis(4-benzoic acid) porphyrin catalyze peroxynitrite-dependent nitration of aromatics.
Peroxynitrite is a powerful oxidant formed in biological systems from the reaction of nitrogen monoxide and superoxide and is capable of nitrating phenols at neutral pH and ambient temperature. This peroxynitrite-mediated nitration is catalyzed by a number of Lewis acids, including CO2 and transition-metal ion complexes. Here we studied the effect of ternary copper-(II) complexes constituted by a 1,10-phenanthroline and an amino acid as ligands. All the complexes studied accelerate both the decomposition of peroxynitrite and its nitration of 4-hydroxyphenylacetic acid at pH > 7. The rate of these reactions depends on the copper complex concentration in a hyperbolic plus linear manner. The yield of nitrated products increases up to 2.6-fold with respect to proton-catalyzed nitration and has a dependency on the concentration of copper complexes which follows the same function as observed for the rate constants. The manganese porphyrin complex, Mn(III)tetrakis(4-benzoic acid)porphyrin [Mn(tbap)], also promoted peroxynitrite-mediated nitration with an even higher yield (4-fold increase) than the ternary copper complexes. At pH = 7.5 +/- 0.2 the catalytic behavior of the copper complexes can be linearly correlated with the pKa of the phenanthroline present as a ligand, implying that a peroxynitrite anion is coordinated to the copper ion prior to the nitration reaction. These observations may prove valuable to understand the biological effects of these transition-metal complexes (i.e., copper and manganese) that can mimic superoxide dismutase activity and, in the case of the ternary copper complexes, show antineoplastic activity.


Injury measurement properties of serum interleukin-6 following lumbar decompression surgery.
Circulating interleukin-6 (IL-6) is frequently used to study surgical injury and inflammation. Measurement properties of serum IL-6 were examined following lumbar decompression surgery (LDS), including time course, sensitivity, and validity for detecting muscle trauma in comparison to the muscle cytoplasmic protein creatine kinase (CK). Seven women and seven men had serial blood samples taken in the preoperative waiting areas, immediately after surgery, at 6, 12, 24, 48 h, 4 d, and at 6 to 7 d. Lumbar surgeries were single level, decompression, with laminotomy. Time to peak serum IL-6 varied across individuals (range 6 to 48 h). However, the higher of two samples drawn within the sensitive time window (6 to 24 h) had a strong correlation with peak IL-6 (r = 0.99, P < 0.001). There was a moderate correlation between the rise in serum IL-6 and rise in serum CK, r = 0.56, P < 0.05. T-tests revealed that group mean IL-6 was significantly elevated at only one serial time point (6 h), whereas group mean CK was significantly elevated at three serial time points (6, 12, 24 h) and approached significant elevation as late as 48 h (P = 0.07). Women had lower CK concentrations at 6 and 24 h but gender differences on IL-6 were not statistically significant. The serum IL-6 response to LDS injury can be captured in a practical manner, despite individual variability in time course. Inclusion of CK measurement may improve sensitivity to the muscle trauma component of an overall injury.


Disposal and disease rates in 340 British dairy herds.
Data derived from 340 dairy herds, mainly in southern England, between April 1998 and March 1999, showed that the average total culling rate was 22.1 per cent, with 5.6 per cent for infertility, 3.6 per cent for mastitis, 1.7 per cent for lameness, 2.0 per cent for poor milk yield, 3.7 per cent for age and 5.5 per cent for miscellaneous reasons which included death. The average annual rate of assisted calvings was 8.7 per cent, of injury 0.9 per cent, digestive disease 1.3 per cent ketosis 0.4 per cent, hypomagnesaemia 0.7 per cent, hypocalcaemia 5.3 per cent, mastitis 36.6 per cent, and lameness 23.7 per cent. There was a significant association (P<0.001) between higher rates of mastitis in cows housed in straw yards as opposed to cubicles and also between higher rates of lameness in cows housed in cubicles as opposed to yards (P<0.015). However, there were farms with low rates of mastitis in cows kept in straw yards and low rates of lameness in cows kept in cubicles. Larger herds tended to have more problems with lameness and higher bulk milk somatic cell counts (BMSCC). There was a positive association between BMSCC and mastitis rate.


Effect of 2-hydroxypropyl-beta-cyclodextrin on percutaneous absorption of methyl paraben.
A potential use of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) to solubilize methyl paraben and to suppress its percutaneous absorption was examined, and compared with nonionic surfactant HCO-60. HP-beta-CyD significantly increased the solubility of methyl paraben in water, where the apparent 1:1 stability constant of the soluble complex was determined to be 2150 M-1. The in-vitro cutaneous permeability of methyl paraben through an isolated skin of hairless mouse was suppressed by HP-beta-CyD, thus promoting the bioconversion of methyl paraben to the less toxic metabolite, p-hydroxybenzoic acid (p-HBA) in the epidermis. These effects of HP-beta-CyD were greater than those of HCO-60. HP-beta-CyD (2% w/v) reduced the in-vivo percutaneous absorption of methyl paraben by 66% 24 h after the topical application of a solution containing [14C]methyl paraben to hairless mouse skin. Additionally, the percutaneous absorption of [14C]HP-beta-CyD was confirmed to be extremely low. These results suggest that HP-beta-CyD is useful in liquid preparations of methyl paraben for topical application.


Self-control and impulsiveness with asynchronous presentation of reinforcement schedules.
IN DISCRETE TRIALS, PIGEONS WERE PRESENTED WITH TWO ALTERNATIVES: to wait for a larger reinforcer, or to respond and obtain a smaller reinforcer immediately. The choice of the former was defined as self-control, and the choice of the latter as impulsiveness. The stimulus that set the opportunity for an impulsive choice was presented after a set interval from the onset of the stimulus that signaled the waiting period. That interval increased or decreased from session to session so that the opportunity for an impulsive choice became available either more removed from or closer in time to the presentation of the larger reinforcer. In three separate conditions, the larger reinforcer was delivered according to either a fixed interval (FI) schedule, a fixed time (FT) schedule, or a differential reinforcement of other behavior (DRO) schedule. The results showed that impulsive choices increased as the opportunity for such a choice was more distant in time from presentation of the larger reinforcer. Although the schedule of the larger reinforcer affected the rate of response in the waiting period, the responses themselves had no effect on choice unless the responses postponed presentation of the larger reinforcer.


Isolation and purification of chloroplastic spinach (Spinacia oleracea) sedoheptulose-1,7-bisphosphatase.
Higher-plant sedoheptulose-1,7-bisphosphatase was isolated and purified over 200-fold from spinach (Spinacia oleracea) chloroplast stromal extracts to apparent electrophoretic homogeneity by DEAE-Fractogel, molecular sieving on Sephadex G-200 and Blue B dye-matrix affinity chromatography. It is a protein of Mr 66,000, made up of two apparently identical subunits (Mr 35,000). The enzyme is activated by reduced thioredoxin fb in the presence of dithiothreitol. Its specificity towards sedoheptulose 1,7-bisphosphate versus fructose 1,6-bisphosphate is high, but not absolute.


Virus and autoantigen-specific CD4+ T cells are key effectors in a SCID mouse model of EBV-associated post-transplant lymphoproliferative disorders.
Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies.


FDG PET imaging in cystic fibrosis.
Cystic fibrosis (CF) is characterized by persistent neutrophilic lung inflammation that begins early in life and leads to an inexorable progressive loss of lung function over time, causing significant morbidity and mortality. Studies to date support the hypothesis that higher levels of lung inflammation lead to worsening lung dysfunction. However, measuring the extent and severity of lung inflammation in the CF lung is difficult as few lung-specific biomarkers of inflammation can quantify the regional and whole-lung inflammatory burden accurately and reproducibly. PET with (18)F-fluorodeoxyglucose ((18)F-FDG) has shown promise in measuring lung inflammation in both acute and chronic lung diseases. Several studies have now shown that (18)F-FDG uptake may be a useful measure of lung inflammation in CF. The whole-lung rate of (18)F-FDG uptake in stable CF, quantified by the Patlak graphical analysis, appears to correlate with more rapidly declining lung function. Acute exacerbation, on the contrary, leads to focally increased (18)F-FDG uptake, which decreases with antibiotic treatment. These small studies are the first attempts to characterize the patterns of (18)F-FDG uptake in CF and suggest a potential role for (18)F-FDG as a treatment modifiable biomarker of lung inflammation in CF.


Cytochemical relationships and central terminations of a unique population of primary afferent neurons in rat.
Light and electron microscopic immunohistochemical techniques were used to investigate the central projections and colocalization relationships of a subpopulation of primary afferent neurons that were immunolabelled with an antibody (AB893) against rat liver gap junctions. In lumbar dorsal root ganglia AB893-immunoreactivity was seen in 14.5% of all cells and in both small and large size neurons. Colocalization analysis showed that 78% of all AB893-immunoreactive (AB893-IR) neurons contained calcitonin gene-related peptide, while only 7 to 10% contained the calcium binding proteins parvalbumin or calbindin D28k. Among small type B AB893-IR ganglion cells, it was calculated that over 90% contained fluoride-resistant acid phosphatase, while only 1 to 2% contained substance P or somatostatin. Cytochrome oxidase histochemistry revealed light staining in the vast majority of AB893-IR cells. In the dorsal horn of the spinal cord the antibody labelled fibers in the dorsal root, Lissauer's tract, lamina I and lamina II. Isolated immunoreactive fiber bundles were arranged in sheets spanning most of lamina II. Immunoreactive fibers were depleted from the dorsal horn after dorsal rhizotomy or neonatal capsaicin treatment. Ultrastructural examination showed that AB893-IR fibers were composed of closely associated clusters of 2 to 5 unmyelinated fibers each ranging from 0.1-0.4 microns in diameter. Immunoreactivity was distributed intermittently along the cytoplasmic membrane of axons and en passant sinusoid terminals located centrally within the fiber clusters, as well as along axonal membranes adjacent to the central axon or terminal. The results suggest that the immunoreactive fibers in lamina II of the dorsal horn originate from a subpopulation of AB893-IR neurons that contain FRAP and give rise to unmyelinated axons.


Amelioration of dextran sulfate sodium-induced colitis by autoinducer-2-deficient Lactiplantibacillus plantarum is mediated by anti-inflammatory effects and alleviation of dysbiosis of the gut microbiota.
Lactic acid bacteria (LAB) attenuate dextran sulfate sodium (DSS)-induced colitis in mice by restoring gut flora homeostasis and modulating the immune response. Because synchronous behavior can be controlled by autoinducer-2 (AI-2)/LuxS-mediated quorum sensing, the Caco-2 cell model and DSS-induced model in C57BL/6 mice were used to explore the unknown effects of these communications involving AI-2 among various intestinal symbiotic species. The results of the cell viability and lactate dehydrogenase leakage assays indicated that the tested strains (the wild-type strains and AI-2-deficient mutants) were characterized by equal cytoprotection from hydrogen peroxide-induced injury independently of AI-2. The results of the assays of multiple indicators and proinflammatory cytokines characteristic for the symptoms of colitis in mice showed that oral administration of AI-2-deficient mutants for 7 days was more effective in ameliorating inflammation than the treatment with the wild-type strains. The treatment with AI-2-deficient mutants enriched potential probiotics (e.g., Lactobacillaceae) and controlled the proliferation of potentially harmful bacteria (e.g., Helicobacteraceae) to achieve the transformation of intestinal flora. These mutants regulated short-chain fatty acids and the intestinal epithelial barrier, thereby promoting the maintenance of relatively favorable intestinal homeostasis. These results demonstrated that the AI-2-deficient mutants provided a more pronounced ameliorative effect on colitis in a mouse model, suggesting that the background of the LAB effect is associated with the alterations in colonic flora induced by AI-2.


The case of the 'Spurious Drugs Kingpin': shifting pills in Chennai, India.
This paper recounts the tale of a 'Spurious Drugs Kingpin' and his scandalous business empire of relabelling and recirculating expired medicines in the south Indian city of Chennai. At the time the story broke, in the first half of 2010, questions of drug safety dominated media headlines and public discussion. However, a closer investigation suggests a more complicated picture. While relabelling expired medicines was certainly a crime, it is far from clear if their relabelling and subsequent redistribution constituted a public health danger. If actually existing unsafe drugs did not fuel this drug safety scandal, what did? I argue this case illuminates two things: (1) the illusory nature of certainties about drug safety and (2) how ambiguity about the safety of expired drugs facilitates policing not of relations within the pharmacological world, but instead of social and economic relations. This episode matters because it illuminates how, within apparent attempts to police the safety of circulation of drugs, drugs themselves are neither subject nor object, but instead the ground upon which market battles are waged.


Seeing the wood despite the trees: Exploring human disturbance impact on plant diversity, community structure, and standing biomass in fragmented high Andean forests.
High Andean forests harbor a remarkably high biodiversity and play a key role in providing vital ecosystem services for neighboring cities and settlements. However, they are among the most fragmented and threatened ecosystems in the neotropics. To preserve their unique biodiversity, a deeper understanding of the effects of anthropogenic perturbations on them is urgently needed. Here, we characterized the plant communities of high Andean forest remnants in the hinterland of Bogotá in 32 0.04 ha plots. We assessed the woody vegetation and sampled the understory and epiphytic cover. We gathered data on compositional and structural parameters and compiled a broad array of variables related to anthropogenic disturbance, ranging from local to landscape-wide metrics. We also assessed phylogenetic diversity and functional diversity. We employed nonmetric multidimensional scaling (NMDS) to select meaningful variables in a first step of the analysis. Then, we performed partial redundancy analysis (pRDA) and generalized linear models (GLMs) in order to test how selected environmental and anthropogenic variables are affecting the composition, diversity, and aboveground biomass of these forests. Identified woody vegetation and understory layer communities were characterized by differences in elevation, temperature, and relative humidity, but were also related to different levels of human influence. We found that the increase of human-related disturbance resulted in less phylogenetic diversity and in the phylogenetic clustering of the woody vegetation and in lower aboveground biomass (AGB) values. As to the understory, disturbance was associated with a higher diversity, jointly with a higher phylogenetic dispersion. The most relevant disturbance predictors identified here were as follows: edge effect, proximity of cattle, minimum fragment age, and median patch size. Interestingly, AGB was efficiently predicted by the proportion of late successional species. We therefore recommend the use of AGB and abundance of late successional species as indicators of human disturbance on high Andean forests.


Novel sensitive monoclonal antibody based competitive enzyme-linked immunosorbent assay for the detection of raw and processed bovine beta-casein.
Cow milk protein allergy (CMPA) is the most common childhood food allergy, which can sometimes persist or can newly develop in adulthood with severe symptoms. CMPA's treatment is complete dietary avoidance of milk proteins. To achieve this task, patients have to be aware of milk proteins found as "hidden allergens" in food commodities. In regard to milk proteins, it has been reported that allergenicity of caseins remains unaffected upon heat treatment. For these reasons, we aimed to obtain monoclonal antibodies (mAbs) against native and denatured β-casein, one of the most abundant and antigenic caseins, in order to develop an indirect competitive ELISA (icELISA) to detect and quantify traces of this milk allergen in raw and processed foodstuffs. We developed two specific hybridoma clones, 1H3 and 6A12, which recognized β-casein in its denatured and native conformations by indirect ELISA (iELISA). Cross-reaction analysis by Western blot and iELISA indicated that these mAbs specifically recognized β-casein from bovine and goat milk extracts, while they did not cross-react with proteins present in other food matrixes. These highly specific mAbs enabled the development of sensitive, reliable and reproducible icELISAs to detect and quantify this milk protein allergen in food commodities. The extraction of β-casein from foodstuff was efficiently carried out at 60°C for 15 minutes, using an extraction buffer containing 1% SDS. The present study establishes a valid 1H3 based-icELISA, which allows the detection and quantification -0.29 ppm and 0.80 ppm, respectively- of small amounts of β-casein in raw and processed foods. Furthermore, we were able to detect milk contamination in incurred food samples with the same sensitivity as a commercial sandwich ELISA thus showing that this icELISA constitutes a reliable analytical method for control strategies in food industry and allergy prevention.


Adverse drug reactions of imatinib in patients with chronic myeloid leukemia: A single-center surveillance study.
To monitor the adverse drug reactions (ADRs) associated with imatinib treatment in patients with chronic myeloid leukemia (CML) in a tertiary care hospital. The study was carried out by the Departments of Pharmacology and Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India. The study was carried out from March 2012 to February 2014. The ADRs were reported in a suspected Adverse Drug Reaction Reporting form, provided by the Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Government of India. The ADRs were analyzed for their pattern, causality and severity. A total of 326 ADRs from 81 patients were reported during the study period. The hematological toxicities were much more prominent than the non-hematological toxicities in this study. The prevalence of thrombocytopenia (21.17%) was higher compared with other reactions. Further analysis showed that most of the ADRs were mild to moderate in nature. The causality assessment revealed that the majority of the ADRs belonged to the possible category. The present study in a tertiary care hospital suggests that hematological toxicities are predominant in CML patients treated with imatinib mesylate. The blood and lymphatic system (38.96%) was the most affected, with imatinib therapy and thrombocytopenia (21.17%) being the most commonly encountered ADRs in the present study. Thorough monitoring of ADRs is warranted for better treatment outcomes.


Sedentary Behavior and Health: Broadening the Knowledge Base and Strengthening the Science.
We provide an overview of a recently published, edited book in a rapidly emerging field of research, policy, and practice for physical activity: Sedentary Behavior and Health. In this commentary, we highlight the broad perspectives provided in the 27 chapters of Sedentary Behavior and Health and suggest a research strategy to move the field forward-not only with scientific rigor, but also with breadth of scholarship. The book's chapters provide an overview of the background to and contexts for sedentary behavior and health. They then highlight the importance of understanding health consequences and underlying mechanisms; introduce key measurement technology and analytic strategies; consider sedentary behavior in subpopulations; describe conceptual models and theories to guide sedentary behavior interventions; and explain what is known about interventions in different settings. Considering the breadth of perspectives brought to bear on the field and the plethora of opportunities for research, policy, and practice, we suggest 3 elements of an interdisciplinary research strategy drawing upon the primary knowledge bases of physical activity and health: through the experimental methods of exercise science, through the observational tools of epidemiology, and through the conceptual approaches and methods of behavioral science. A better understanding of the health consequences of sedentary behavior and how they may be influenced can be encompassed by 3 key questions: What changes are needed to most effectively influence sedentary behaviors? What elements of sedentary behavior should be changed to improve health outcomes? What are the feasibility of and the benefits from changing sedentary behavior?


[A tissue specific antigen in rats with malignancies in vitro].
By means of a semiquantitative antigenic analysis in the reaction of precipitation in agar with the use of a monospecific serum, obtained by the authors, dynamical changes have been studied in the content of the tissue-specific antigen in cells of subcutaneous connective tissue in rats: in the original and tripsinzed tissues, in 3, 6, 16-day and 1--2--3 month and malignized cultures, as well. It was found that at the 3, 11--13 day and then in 2--3 months of explantation there was a decrease in the content of the tissue-specific antigen, that is positively correlated with the degree of cell differentiation.


Invasion of reconstituted basement membrane matrix by metastatic human tumor cells.
A gel-like reconstituted basement membrane matrix containing type IV collagen, laminin, entactin, nidogen, and heparan sulfate proteoglycan was used to examine the invasive properties of human HT1080 fibrosarcoma cells. Within several hours after seeding, the tumor cells initiated a random migration, leaving behind channels etched in the surface of the matrix. Eventually the channels became interconnected into a complex network. As the tumor cells proliferated, the channels became filled until the surrounding matrix was gradually dissolved. Cells then migrated outward, forming the typical disorganized cell monolayer normally observed when fibrosarcoma cells are cultured on plastic surfaces. In contrast to the fibrosarcoma cells, normal skin fibroblasts, while able to attach to the matrix, exhibited minimal migration, tracking, and invasion during the same time period. When tumor cells were seeded onto thick layers of matrix, the cells ultimately invaded downward into the matrix, leaving behind open tunnels. At the front of the invading cells, long irregular pseudopodia projected in the direction of movement. Electron microscopy demonstrated these filopodial and lamellopodial projections to directly extend into the surrounding matrix, with focal clearing of the matrix in the immediate vicinity of these invading pseudopodia. Thus, tumor cell invasion of extracellular matrices, including basal lamina, may proceed by the formation of specialized pseudopodia that not only form adhesion contacts with the matrix but also provide an efficient mechanism for the focal hydrolysis of the matrix at the site of directed cell movement.


Coloration and Fire Retardancy of Transparent Wood Composites by Metal Ions.
Transparent wood composites (TWs) offer the possibility of unique coloration effects. A colored transparent wood composite (C-TW) with enhanced fire retardancy was impregnated by metal ion solutions, followed by methyl methacrylate (MMA) impregnation and polymerization. Bleached birch wood with a preserved hierarchical structure acted as a host for metal ions. Cobalt, nickel, copper, and iron metal salts were used. The location and distribution of metal ions in C-TW as well as the mechanical performance, optical properties, and fire retardancy were investigated. The C-TW coloration is tunable by controlling the metal ion species and concentration. The metal ions reduced heat release rates and limited the production of smoke during forced combustion tests. The potential for scaled-up production was verified by fabricating samples with a dimension of 180 × 100 × 1 (l × b × h) mm3.


Comparative Genomic and Transcriptomic Analyses of Mycobacterium kansasii Subtypes Provide New Insights Into Their Pathogenicity and Taxonomy.
Mycobacterium kansasii is an important opportunistic pathogen of humans and has a close phylogenetic relationship with Mycobacterium tuberculosis. Seven subtypes (I-VII) have been identified using molecular biology approaches, of which subtype I is the most frequent causative agent of human disease. To investigate the genotypes and pathogenic components of M. kansasii, we sequenced and compared the complete base-perfect genomes of different M. kansasii subtypes. Our findings support the proposition that M. kansasii "subtypes" I-VI, whose assemblies are currently available, should be considered as different species. Furthermore, we identified the exclusive presence of the espACD operon in M. kansasii subtype I, and we confirmed its role in the pathogenicity of M. kansasii in a cell infection model. The espACD operon is exclusively present in mycobacterial species that induce phagosomal rupture in host phagocytes and is known to be a major determinant of ESX1-mediated virulence in pathogenic mycobacteria. Comparative transcriptome analysis of the M. kansasii I-V strains identified genes potentially associated with virulence. Using a comparative genomics approach, we designed primers for PCR genotyping of M. kansasii subtypes I-V and tested their efficacy using clinically relevant strains of M. kansasii.


A dominant Th epitope in influenza nucleoprotein. Analysis of the fine specificity and functional repertoire of T cells recognizing a single determinant.
The sequence 260-283 of the nucleoprotein (NP) of influenza A virus is an epitope recognized by virus-immune lymph node cells from CBA (H-2k), B6 (H-2b), and B10.S (H-2s) mice. Further analysis shows that there are at least two Th epitopes within this sequence: the one close to the N-terminal (p260-273) is recognized by T cells from CBA and B6 mice while that close to the carboxyl-terminal (p270-283) is a dominant Th determinant in B10.S mice. The fine specificity of the recognition of this epitope by NP-specific T cell clones is also studied. When B10.S mice were infected intranasally or i.v. with live influenza virus, or immunized by different ways with various Ag preparations, P270-283 persistently emerged as a dominant T cell epitope. Immunization of B10.S mice with peptide p270-283 induces T cells with different in vivo functions including class II-restricted cytotoxicity, cognate help for Ag-specific antibody synthesis and delayed type hypersensitivity. This may have important implications for the understanding of the differentiation and classification of subsets of CD4+ T cells. The corresponding sequence of the NP of an equine influenza virus, A/Eq/Prague/56, which has a substitution (leucine to proline) at position 283, was not recognized by the lymph node cells from mice primed with either A/Okuda or A/Eq/Prague. However, the peptide, p270-283(E), representing this sequence induced T cell responses to both human and equine viruses. The data are discussed with respect to the development of viral vaccines.


An Economic Evaluation of Coordinated Specialty Care (CSC) Services for First-Episode Psychosis in the U.S. Public Sector.
Schizophrenia spectrum disorders exert a large and disproportionate economic impact. Early intervention services may be able to alleviate the burden of schizophrenia spectrum disorders on diagnosed individuals, caregivers, and society at large. Economic analyses of observational studies have supported investments in specialized team-based care for early psychosis; however, questions remain regarding the economic viability of first-episode services in the fragmented U.S. healthcare system. The clinic for Specialized Treatment Early in Psychosis (STEP) was established in 2006, to explicitly model a nationally-relevant U.S. public-sector early intervention service. The purpose of this study was to conduct an economic evaluation of STEP, a Coordinated Specialty Care service (CSC) based in a U.S. State-funded community mental health center, relative to usual treatment (UT). Eligible patients were within 5 years of psychosis onset and had no more than 12 weeks of lifetime antipsychotic exposure. Participants were randomized to STEP or UT. The annual per-patient cost of the STEP intervention per se was estimated assuming a steady-state caseload of 30 patients. A cost-offset analysis was conducted to estimate the net value of STEP from a third-party payer perspective. Participant healthcare service utilization was evaluated at 6 months and over the entire 12 months post randomization. Generalized linear model multivariable regressions were used to estimate the effect of STEP on healthcare costs over time, and generate predicted mean costs, which were combined with the per-patient cost of STEP. The annual per-patient cost of STEP was $1,984. STEP participants were significantly less likely to have any inpatient or ED visits; among individuals who did use such services in a given period, the associated costs were significantly lower for STEP participants at month 12. We did not observe a similar effect with regard to other healthcare services. The predicted average total costs were lower for STEP than UT, indicating a net benefit for STEP of $1,029 at month 6 and $2,991 at month 12; however, the differences were not statistically significant. Our findings are promising with regard to the value of STEP to third-party payers.


Upper hemibody and local chest irradiation as consolidation following response to high-dose induction chemotherapy for small cell bronchogenic carcinoma--a pilot study.
Encouraging results of the combination of upper hemibody irradiation (UHBI) and local chest irradiation (LCI) combined withh standard-dose chemotherapy in patients with extensive small cell bronchogenic carcinoma led us to a second pilot study utilizing the same radiation program combined wit high-dose induction chemotherapy. Fourteen patients with small cell bronchogenic carcinoma, five with extensive disease and nine with localized disease, were treated with cyclophosphamide (1.5 g/m2 iv, Days 1 and 22), lomustine (70 mg/m2 orally, Day 1), and methotrexate (15 mg/m2 twice weekly during Weeks 2, 3, 5, and 6). UHBI (600 rads) was given during Week 6 in a single dose and LCI was given during Week 7 (2000 rads/five fractions) to the tumor and mediastinum. Maintenance chemotherapy began in Week 12 with cyclophosphamide (700 mg/m2 iv every 3 weeks) and lomustine (70 mg/m2 orally every 6 weeks). Twelve patients were evaluable for response and toxicity (eight with limited disease). There were three complete response and seven partial responses after induction chemotherapy. After completion of the consolidation radiation therapy, all 12 patients had a response: six complete responses and six partial responses. Acute toxic effects included nausea and vomiting in eight patients, fever in five, and hypotension and angina in one. Subacute toxic effects included nausea, vomiting, and dehydration in two patients who required hospitalization, prolonged aplasia in one, reversible radiation esophagitis in three. Three patients had radiation pneumonitis including one with bilateral diffuse disease that led to death from respiratory failure. Only two of 12 patients received their maintenance therapy on schedule. Treatment failures occurred within the LCI field in seven patients and in distant metastatic sites in six. The median time to first relapse was 7 months and the median survival was 9 months. Because of toxicity, treatment delays, and poor survival in this group of patients, we cannot recommend this combined modality approach.


30 years of colposcopic studies: validity of local destructives treatments.
The effectiveness of local destructive treatments (LDT) applied in patients due to cervical pathology oncogenic risk (OR), were followed and verified in 396 patients who came to our attention, focusing on the type of pathology, type of treatment received, diagnosis clinical evolutionary, and results of the new study applying polymerase chain reaction (PCR), and above all, the time between the diagnosis, treatment, and PCR findings. The clinical evolution of the same reports achieved a healing rate of 82% followed by persistence 8.3%; improvement 4.8%, recurrence 2.8%, and only one case of progression 0.2%. The elapsed time in initial care and treatment was almost immediate, as the pathology diagnosis was considered on an emergency basis. Successive controls of these indicated that 119 studies of routine colposcopy were carried out, on an average of the first three years and with a maximum follow up of 30 years, with over 30 routine colposcopies that achieved healing in most of these. In 2011 and 2012, we added to the usual diagnostic methodology, molecular biology, and 119 studies were performed in those patients, resulting in only five negative cases. Most studies were classified as high risk papillomavirus (HR-HPV), corresponding to subtypes 31, 35, 18, and 16.


Gastroprotective and antioxidant effects of Eremurus spectabilis Bieb. methanol extract and its isolated component isoorientin on indomethacin induced gastric ulcers in rats1.
To investigate the gastroprotective effect of methanol extract of E. spectabilis and its major component isoorientin. Effects of isoorientin and methanol extract of E. spectabilis were investigated in indomethacin-induced gastric damage model on rats. Famotidine was used as the standard antiulcer drug. Numerical density of ulcer areas and oxidative status were determined on stomach tissues of rats. All doses of isoorientin and methanol extract decreased MDA level and increased SOD activity and GSH levels in the stomach tissue of rats. When numerical density of ulcer areas were analized, the 500 mg/kg dose of methanol extract (84%) exhibited a similar effect to 20 mg/kg dose of standart drug famotidine (87%). The gastroprotective effects of E. spectabilis and its major constituent isoorientin in rats for the first time. Detailed analyses suggested that potential antioxidant activity of both plant extract and isoorientin mediates the gastroprotective effect.


[Pathogenic mechanisms of proatherogenic changes in pregnant women with concomitant obesity].
The concentration of insulin, high sensitivity C-reactive protein (CRP) and indices of lipid metabolism (concentrations of triacylglycerols, total cholesterol, cholesterol of low density lipoproteins and cholesterol of very low density lipoproteins) in women with concomitant obesity in the second trimester of pregnancy were studied. Changes of the lipid profile in the pregnant women with concomitant obesity indicate development of type IV hyperlipoproteinemia. Concentrations of insulin and CRP in the blood serum of the pregnant women with obesity were respectively 92.1% and 62.5% higher than in the control group. On the basis of literature data and our own research it was concluded that the complex of the metabolic changes (insulin resistance, dislipidemia, endothelial dysfunction, systemic inflammation) in pregnant women with obesity promotes development of proatherogenic changes.


Electrophysiological evidence for an inhibitory action of diazepam upon cat brain cortex.
Diazepam was shown to increase postexcitatory inhibition within the brain cortex as revealed by its influence upon the recovery cycles both of intracortical and primary responses. The specific interrelationship between diazepam and some drugs affecting brain GABA level suggests the possibility of a GABA mediated mechanism in the diazepam effect. The sensitivity of the brain cortex to diazepam is not lower than that of the amygdala and significantly higher than that of the hippocampus.


Fluidic resistance control enables high-throughput establishment of mixed-species biofilms.
Bacteria often live in communities of mixed species embedded in a self-produced extracellular matrix of polysaccharides, proteins and DNA, termed biofilms. The BioFlux microfluidic flow system is useful for studying biofilm formation in different media under flow. However, analyzing the architecture and maturation of biofilms under flow requires a proper seeding, which can prove difficult when working with bacteria of different sizes, motile bacteria or aiming for a high number of replicates. Here we developed an efficient protocol that exploits viscosity tuning and seeding indicator dyes to improve seeding and allow for high-throughput examination and visualization of consistent mono- and mixed-species biofilm developments under flow.


Herbal natural products as a source of monoamine oxidase inhibitors: a review.
Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nervous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neurotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturalization, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitoring MAO activity and its inhibitor screening of bioactive natural products.


Effects of selective and non-selective COX inhibitors on antigen-induced release of prostanoid mediators and bronchoconstriction in the isolated perfused and ventilated guinea pig lung.
The contribution of cycloxygenase (COX)-1 and COX-2 in antigen-induced release of mediators and ensuing bronchoconstriction was investigated in the isolated perfused guinea pig lung (IPL). Antigen challenge with ovalbumin (OVA) of lungs from actively sensitised animals induced release of thromboxane (TX)A(2), prostaglandin (PG)D(2), PGF(2)(alpha), PGI(2) and PGE(2), measured in the lung effluent as immunoreactive TXB(2), PGD(2)-MOX, PGF(2)(alpha), 6-keto PGF(1)(alpha) and PGE(2), respectively. This release was abolished by the non-selective COX inhibitor flurbiprofen (10 microM). In contrast, neither the selective COX-1 inhibitor FR122047 nor the selective COX-2 inhibitor celecoxib (10 microM each) significantly inhibited the OVA-induced bronchoconstriction or release of COX products, except for PGD(2). Another non-selective COX inhibitor, diclofenac (10 microM) also significantly inhibited antigen-induced bronchoconstriction. The data suggest that both COX isoenzymes, COX-1 and COX-2 contribute to the immediate antigen-induced generation of prostanoids in IPL and that the COX-1 and COX-2 activities are not associated with different profiles of prostanoid end products.


Protective effects of garlic extract and vitamin C against in vivo cypermethrin-induced cytogenetic damage in rat bone-marrow.
The cytogenetic damage inflicted by the synthetic pyrethroid insecticide cypermethrin (CYP) on the bone-marrow of male white rats, as well as possible protective role of two natural elements: garlic extract (GRE, 500mg/kg) and vitamin C (VTC, 20mg/kg) against the mutagenic potential of the insecticide were assessed. CYP was orally intubated in a single treatment (1/2 LD(50)) or in repeated treatments (1/5 LD(50) daily, for 5 successive days), either alone, or concomitantly with repeated oral intubations (5 successive days) of each individual putative protector, or with their combination (GRE or/and VTC). One hundred and twenty male rats were divided over into five groups of each 24 animals. The groups received nothing, a single dose or repeated treatments with insecticide alone, or associated with putative natural elements, separately or in combinations. Animals were sacrificed at their scheduled times and their femoral bone-marrows were flushed out to be utilized in the micronucleus test and metaphase chromosomal aberration assay. The results show that CYP administration significantly induced clastogenic effects, as revealed by the significant increase in the mean frequencies of micronucleated polychromatic erythrocytes and various structural chromosomal aberrations in bone-marrow metaphase cells of all groups of treated rats. On the other hand, this investigation clearly revealed the protective role of GRE and VTC, either each alone or in combination, against the mutagenic potential of cypermethrin: the garlic extract was often more efficient in its protective action against the insecticide toxicity than vitamin C. while the combination of both natural elements produced, in most cases, a more pronounced protective effect than when each was administered alone.


The distribution and some effects of polychlorinated biphenyls (Aroclor 1254) in cockerels during prolonged feeding trial.
A ration containing 500 ppm of polychlorinated biphenyls (PCB) was fed to one month old cockerels for periods up to 12 weeks. The distribution of PCB was determined in the brain, liver, kidneys and blood as well as in the muscular and adipose tissues. Tissue concentrations of PCB increased linearly with time. Small changes were detected on the chromatograms of the liver, fat and blood extracts.A significant decrease in the size of the combs and testicles in PCB-treated birds was noted. This decrease appeared as early as one week after the start of PCB administration.


Activation of coagulation and tissue fibrin deposition in experimental influenza in ferrets.
Epidemiological studies relate influenza infection with vascular diseases like myocardial infarction. The hypothesis that influenza infection has procoagulant effects on humans has been investigated by experimental animal models. However, these studies often made use of animal models only susceptible to adapted influenza viruses (mouse adapted influenza strains) or remained inconclusive. Therefore, we decided to study the influence of infection with human influenza virus isolates on coagulation in the well-established ferret influenza model. After infection with either a seasonal-, pandemic- or highly pathogenic avian influenza (HPAI-H5N1) virus strain infected animals showed alterations in hemostasis compared to the control animals. Specifically on day 4 post infection, a four second rise in both PT and aPTT was observed. D-dimer concentrations increased in all 3 influenza groups with the highest concentrations in the pandemic influenza group. Von Willebrand factor activity levels increased early in infection suggesting endothelial cell activation. Mean thrombin-antithrombin complex levels increased in both pandemic and HPAI-H5N1 virus infected ferrets. At tissue level, fibrin staining showed intracapillary fibrin deposition especially in HPAI-H5N1 virus infected ferrets. This study showed hemostatic alterations both at the circulatory and at the tissue level upon infection with different influenza viruses in an animal model closely mimicking human influenza virus infection. Alterations largely correlated with the severity of the respective influenza virus infections.


Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India.
Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health. Fourteen sites in 7 countries within sub-Saharan Africa and India. The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. Two thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. ClinicalTrials.gov: NCT01061151; closed to follow-up.


A new parameter estimation method for solute transport in a column.
To study contaminant transport in groundwater, an essential requirement is robust and accurate estimation of the transport parameters such as dispersion coefficient. The commonly used inverse error function method (IEFM) may cause unacceptable errors in dispersion coefficient estimation using the breakthrough curves (BTCs) data. We prove that the random error in the measured concentrations, which might be described by a normal distribution, would no longer follow the normal distribution after the IEFM transformation. In this study, we proposed a new method using the weighted least squares method (WLSM) to estimate the dispersion coefficient and velocity of groundwater. The weights were calculated based on the slope of the observed BTCs. We tested the new method against other methods such as genetic algorithm and CXTFIT program and found great agreement. This new method acknowledged different characteristics of solute transport at early, intermediate, and late time stages and divided BTCs into three sections for analysis. The developed method was applied to interpret three column tracer experiments by introducing continuous, constant-concentration of sodium chloride (NaCl) into columns filled with sand, gravel, and sand-gravel media. This study showed that IEFM performed well only when the observed data points were located in the linear (intermediate time) section of BTCs; it performed poorly when data points were in the early and late time stages. The new WLSM method, however, performed well for data points scattering over the entire BTCs and appeared promising in parameter estimation for solute transport in a column.


Cohesin gene mutations in tumorigenesis: from discovery to clinical significance.
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.


Growth factor inhibition: potential role in the etiopathogenesis of osteoarthritis.
Growth factors are small proteins that regulate cellular function. Some growth factors, including insulin like growth factor-1 and transforming growth factor-beta play an anabolic role in articular cartilage. The loss of articular cartilage that occurs in osteoarthritis may reflect, in part, an insufficiency of such factors. Recent evidence suggests that inhibition of these growth factors may contribute to the disease process in osteoarthritis. Inhibitors identified to date include binding proteins, cytokines, mechanical factors, and nutritional status. The mechanisms underlying the actions and interactions of these regulatory factors are beginning to be elucidated and may have implications for the development of new approaches to the treatment of osteoarthritis.


Crystal structures of SarA, a pleiotropic regulator of virulence genes in S. aureus.
Staphylococcus aureus is a major human pathogen, the potency of which can be attributed to the regulated expression of an impressive array of virulence determinants. A key pleiotropic transcriptional regulator of these virulence factors is SarA, which is encoded by the sar (staphylococcal accessory regulator) locus. SarA was characterized initially as an activator of a second virulence regulatory locus, agr, through its interaction with a series of heptad repeats (AGTTAAG) within the agr promoter. Subsequent DNA-binding studies have revealed that SarA binds readily to multiple AT-rich sequences of variable lengths. Here we describe the crystal structure of SarA and a SarA-DNA complex at resolutions of 2.50 A and 2.95 A, respectively. SarA has a fold consisting of a four-helix core region and 'inducible regions' comprising a beta-hairpin and a carboxy-terminal loop. On binding DNA, the inducible regions undergo marked conformational changes, becoming part of extended and distorted alpha-helices, which encase the DNA. SarA recognizes an AT-rich site in which the DNA is highly overwound and adopts a D-DNA-like conformation by indirect readout. These structures thus provide insight into SarA-mediated transcription regulation.


Tuning Active Site Flexibility by Defect Engineering of Graphene Ribbon Edge-hosted Fe-N3 Sites.
Nitrogen-doped, carbon-supported transition metal catalysts are excellent for several reactions. Structural engineering of metal-Nx sites to boost catalytic activity is rarely studied. Here, we demonstrate that the structural flexibility of Fe-N3 site is vital for tuning the electronic structure of Fe atoms and regulating the catalytic transfer hydrogenation (CTH) activity. By introducing carbon defects, we construct Fe-N3 sites with varying Fe-N bond lengths distinguishable by X-ray absorption spectroscopy. We investigate the CTH activity by density functional theory and microkinetic calculations and reveal that the vertical displacement of the Fe atom out of the plane of the support, induced by the Fe-N3 distortion, raises the Fe [[EQUATION]]orbital and strengthens binding. We propose that the activity is controlled by the relaxation of the reconstructed site, which is further affected by Fe-N bond length, an excellent activity descriptor. We elucidate the origin of the CTH activity and principles for high-performing Fe-N-C catalysts by defect engineering.


Endothelial dysfunction and antioxidants.
The vascular endothelium plays a crucial role in the physiology of blood vessels and the pathological processes of atherosclerotic disease and acute coronary syndromes. Endothelial dysfunction is the core problem; it is an impairment of endothelium-dependent vasorelaxation caused by a loss of nitric oxide activity in the vessel wall, which results in impairment in the regulation of vascular homeostasis. Further understanding of its mechanisms of action and possible therapeutic targets will be of great importance. The group of antioxidant vitamins, A, C and E, would seem uniquely situated to reduce cardiovascular events by improving endothelial function by reducing the concentration of reactive oxygen species in the vessel wall and by preventing oxidative modification of low-density lipoprotein. Unfortunately, despite extensive studies in both observational and randomized trials, the weight of evidence points to little or no benefit from antioxidant therapy.


Controlled Release of Metformin Hydrochloride from Core-Shell Nanofibers with Fish Sarcoplasmic Protein.
Background and Objectives: A coaxial electrospinning technique was used to produce core/shell nanofibers of a polylactic acid (PLA) as a shell and a polyvinyl alcohol (PVA) containing metformin hydrochloride (MH) as a core. Materials and Methods: Fish sarcoplasmic protein (FSP) was extracted from fresh bonito and incorporated into nanofiber at various concentrations to investigate the influence on properties of the coaxial nanofibers. The morphology, chemical structure and thermal properties of the nanofibers were studied. Results: The results show that uniform and bead-free structured nanofibers with diameters ranging from 621 nm to 681 nm were obtained. A differential scanning calorimetry (DSC) analysis shows that FSP had a reducing effect on the crystallinity of the nanofibers. Furthermore, the drug release profile of electrospun fibers was analyzed using the spectrophotometric method. Conclusions: The nanofibers showed prolonged and sustained release and the first order kinetic seems to be more suitable to describe the release. MTT assay suggests that the produced drug and protein loaded coaxial nanofibers are non-toxic and enhance cell attachment. Thus, these results demonstrate that the produced nanofibers had the potential to be used for diabetic wound healing applications.


Activation of human Vgamma9Vdelta2 T cells by a Brucella suis non-peptidic fraction impairs bacterial intracellular multiplication in monocytic infected cells.
Human gamma delta T cells are considered to play an important role in the early response to infection with intracellular pathogens. Evidence has been presented that the percentage of gamma delta T cells with Vgamma9Vdelta2 phenotype is dramatically increased in the peripheral blood of patients with acute brucellosis. This specific gd T-cell subpopulation is known to be activated by small non-peptidic molecules that can either be produced by the pathogen itself or released from damaged cells after infection. In the present work we provide evidence that Vgamma9Vdelta2 T lymphocytes from peripheral blood mononuclear cells of healthy donors can be specifically activated by non-peptidic low-molecular-weight compound(s) from Brucella suis lysate. Moreover, we show that Vgamma9Vdelta2 T cells activated by this B. suis fraction produce tumour necrosis factor-alpha and interferon-gamma, which reduce bacterial multiplication inside infected cells.