Can laser speckle flowmetry be made a quantitative tool?
The ultimate objective of laser speckle flowmetry (and a host of specific implementations such as laser speckle contrast analysis, LASCA or LSCA; laser speckle spatial contrast analysis, LSSCA; laser speckle temporal contrast analysis, LSTCA; etc.) is to infer flow velocity from the observed speckle contrast. Despite numerous demonstrations over the past 25 years of such a qualitative relationship, no convincing quantitative relationship has been proven. One reason is a persistent mathematical error that has been propagated by a host of workers; another is a misconception about the proper autocorrelation function for ordered flow. Still another hindrance has been uncertainty in the specific relationship between decorrelation time and local flow velocity. Herein we attempt to dispel some of these errors and misconceptions with the intent of turning laser speckle flowmetry into a quantitative tool. Specifically we review the underlying theory, explore the impact of various analytic models for relating measured intensity fluctuations to scatterer motion, and address some of the practical issues associated with the measurement and subsequent data processing.


Immunofluorescence analysis of the basement membrane zone components in human anagen hair follicles.
The ultrastructure and constituent components of the basement membrane zone (BMZ) of the interfollicular epidermis have been well characterized. However, little is known about the junctions between dermal papilla and the surrounding epithelial cells of the hair bulb, as well as those junctions between connective tissues and epithelial cells outside the hair follicle. In the present study, immunofluorescence was used to determine the expression of various BMZ components, particularly plectin, BP230, BP180, alpha6beta4 integrin, laminin 5 and type VII collagen, in anagen hair follicles from human scalp. All the BMZ components examined showed essentially the same immunofluorescence staining pattern. Specifically, staining of the upper portion of the hair follicle demonstrated expression of all BMZ components with a labeling intensity similar to that found in the interfollicular epidermis. Staining in the lower portion of the hair follicle, however, was markedly different: all the BMZ components showed a gradual decrease in staining intensity. Particularly, outside the hair bulb, the linear staining was diminished and even discontinuous in some areas. Finally, between dermal papilla and epithelial cells inside the hair bulb, there was a strong immunoreactivity for all the BMZ components except for BP230, which was completely negative. The present study also confirmed a previous reported ultrastructural finding that hemidesmosomes are not apparent in the hair bulb's exterior BMZ nor in the dermal papilla junctions. Instead, peculiar cloudy materials were seen in both the lamina densa and the adjacent epithelium outside the hair bulb. Taken together, the diminished expression of all the BMZ components outside the hair bulb, as well as the complete absence of BP230 at the dermal papilla junction, seem to be responsible for the incomplete ultrastructure of hemidesmosomes in these regions. Furthermore, the results in the present study led us to speculate that the expression of BMZ components inside and outside the hair bulb are markedly decreased in the transient regions of the hair follicle as compared with their expression in the permanent region, signified by the upper portion of the hair follicle. When the hair follicle moves upward in catagen or downward in anagen, the complete structure of the hemidesmosome may stabilize the upper portion to the surrounding connective tissues, while the incomplete hemidesmosome may facilitate the movement of the transient region.


Simplified particulate model for coarse-grained hemodynamics simulations.
Human blood flow is a multiscale problem: in first approximation, blood is a dense suspension of plasma and deformable red cells. Physiological vessel diameters range from about one to thousands of cell radii. Current computational models either involve a homogeneous fluid and cannot track particulate effects or describe a relatively small number of cells with high resolution but are incapable to reach relevant time and length scales. Our approach is to simplify much further than existing particulate models. We combine well-established methods from other areas of physics in order to find the essential ingredients for a minimalist description that still recovers hemorheology. These ingredients are a lattice Boltzmann method describing rigid particle suspensions to account for hydrodynamic long-range interactions and-in order to describe the more complex short-range behavior of cells-anisotropic model potentials known from molecular-dynamics simulations. Paying detailedness, we achieve an efficient and scalable implementation which is crucial for our ultimate goal: establishing a link between the collective behavior of millions of cells and the macroscopic properties of blood in realistic flow situations. In this paper we present our model and demonstrate its applicability to conditions typical for the microvasculature.


Current and Emerging Pharmacotherapy for Fibromyalgia.
Introduction. Fibromyalgia syndrome (FMS) is a pain disorder with an estimated prevalence of 1-5%. It is associated with a variety of somatic and psychological disorders. Its exact pathogenesis is still unclear but is involved with neural oversensitization and decreased conditioned pain modulation (CPM), combined with cognitive dysfunction, memory impairment, and altered information processing. Connectivity between brain areas involved in pain processing, alertness, and cognition is increased in the syndrome, making its pharmacologic therapy complex. Only three drugs, pregabalin, duloxetine, and milnacipran are currently FDA-approved for FM treatment, but many other agents have been tested over the years, with varying efficacy. Areas Covered. The purpose of this review is to summarize current clinical experience with different pharmacologic treatments used for fibromyalgia and introduce future perspectives in developing therapies. Expert Opinion. Future insights into the fields of cannabinoid and opioid research, as well as an integrative approach towards the incorporation of genetics and functional imaging combined with additional fields of research relevant towards the study of complex CNS disorders, are likely to lead to new developments of novel tailor-made treatments for FMS patients.


Prolactin (PRL) receptor gene expression in mouse adipose tissue: increases during lactation and in PRL-transgenic mice.
There are indications that PRL may exert important metabolic actions on adipose tissue in different species. However, with the exception of birds, the receptor has not been identified in white adipose tissue. The present study was designed to examine the possible expression and regulation of the PRL receptor (PRLR) in mouse adipose tissue. The long PRLR messenger RNA (mRNA) splice form (L-PRLR) and two short splice forms (S2- and S3-PRLR) were detected in mouse adipose tissue by RT-PCR. Furthermore, L-PRLR mRNA was detected by ribonuclease protection assay. Immunoreactive PRLR with a relative molecular mass of 95,000 was revealed by immunoblotting. Furthermore, L-PRLR mRNA expression was demonstrated in primary isolated adipocytes. In mouse adipose tissue, the level of L-PRLR mRNA expression increased 2.3-fold during lactation compared with those in virgin and pregnant mice. In contrast, in the liver the expression of L-PRLR increased 3.4-fold during pregnancy compared with those in virgin and lactating mice. When comparing the levels of L-PRLR expression in virgin female and male mice, no difference was detected in adipose tissue. However, in virgin female liver the expression was 4.5-fold higher than that in male liver. As PRL up-regulates its own receptor in some tissues, we analyzed L-PRLR expression in PRL-transgenic female and male mice. In PRL-transgenic mice L-PRLR expression was significantly increased in both adipose tissue (1.4-fold in females and 2.4-fold in males) and liver (1.9-fold in females and 2.7-fold in males) compared with that in control mice. Furthermore, in female PRL-transgenic mice retroperitoneal adipose tissue was decreased in weight compared with that in control mice. However, no difference was detected when comparing the masses of parametrial adipose tissue. Our results suggest a direct role for PRL, mediated by PRLR, in modulating physiological events in adipose tissue.


Extent of propionate metabolism during absorption from the bovine ruminoreticulum.
1. Solutions containing acetate, [2-(14)C]propionate and butyrate were placed into the ruminoreticulum of calves to measure the extent to which propionate is metabolized by ruminoreticulum epithelium. In response to five different combinations of pH and total volatile fatty acid concentrations, propionate absorption rates ranged from 89 to 341mmol/h. 2. The extent of propionate conversion into lactate, calculated from both concentration and specific radioactivity in portal and arterial blood, averaged 4.9 (range 2.5-9.1)%. 3. Circulating glucose synthesized from propionate had a higher specific radioactivity than arterial lactate and was converted into lactate by gastrointestinal tissues. Thus conversion of propionate into lactate was overestimated but was corrected to average 2.3 (1.0-4.6)%. 4. The estimates of propionate conversion into lactate were negatively correlated with its rate of absorption.


Congenital mesoblastic nephroma: a clinicoradiologic study of 17 cases representing the pathologic spectrum of the disease.
Congenital mesoblastic nephroma (CMN) is a rare infantile renal tumor with a generally excellent prognosis. We describe 17 tumors that fit into the pathologic spectrum of CMN proposed by Beckwith, which ranges from benign renal tumors, through atypical "gray zone" lesions of more aggressive potential, to "crossover" tumors akin to clear cell sarcoma of kidney. Nine patients with histologically typical CMN were significantly younger and had smaller tumors than did eight patients with atypical CMN. Clinical features did not differ in the two groups of patients. A distinctive "ring sign" on renal sonography was commonly seen in patients with typical intrarenal CMN. All 17 patients were alive with no evidence of disease at a mean follow-up of 10 years. Nephrectomy was adequate therapy for younger infants and for those with typical CMN. Nephrectomy was probably also adequate therapy for infants 3 months of age or younger with atypical CMN, even if the tumor extended to the surgical resection margins and into the perinephric connective tissues. Adjuvant chemotherapy or radiation or both should be reserved for patients older than 3 months who have grossly unresected tumors and for those patients whose tumors have an unequivocally malignant histologic appearance or evidence of aggressive biologic behavior.


Who should receive a statin drug to lower cardiovascular risk? Does the drug and the dose of the drug matter?
As the numbers of completed outcomes based clinical trials evaluating the use of statin drugs for the management of cardiovascular risk continue to increase, it is clear that the numbers of patients that may benefit from these drugs continues to grow. The recently published studies are reviewed in this summary. The distinction is made between patients requiring either primary or secondary cardiovascular preventive management. The review identifies the increasing numbers of patients who may benefit from the use of statins as primary preventive management, and the changing concepts of the utilization of statin drugs for secondary preventive management, including the more aggressive titration of the drugs to provide incremental improvement in patient outcomes. Available data on the use of statins in the elderly patient are reviewed, and observations are made regarding the intrinsic properties and adverse effects of the drugs.


Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.
The prevalence of transsexualism is thought to differ among socio-geographic backgrounds, and little is known about its prevalence in Japan. Polycystic ovary syndrome (PCOS), which is known to be associated with insulin resistance and metabolic syndrome, is often seen in female-to-male (FTM) transsexual patients. Consequently, detection of PCOS is an important part of health care for these individuals. The purpose of this study was to assess the prevalence of transsexuality in Japan, as well as the incidences of PCOS and insulin resistance among Japanese FTM transsexual patients. One hundred four male-to-female (MTF) and 238 FTM Japanese transsexual patients were studied. Medical histories, including histories of menstrual cycling and hormone treatment, were taken. To exclude other diseases, such as congenital adrenal hyperplasia and hormone-secreting tumors, thorough medical assessments, including transvaginal or transrectal ultrasonography and measurement of serum hormone levels and insulin resistance indexes, were performed. The diagnosis of PCOS was based on the Rotterdam 2003 criteria. Based on demographic statistics, the prevalences of MTF and FTM transsexuality are about 3.97 and 8.20 per 100,000 people, respectively, making the MTF-to-FTM ratio about 1:2. Of the FTM transsexual patients studied, 128 had not taken hormones before their initial assessment (untreated group); the remaining 50 self-administered androgen. Among the untreated group, 32.0% were diagnosed with PCOS, 30.1% were insulin-resistant, and 31.1% showed hypoadiponectinemia. The sex ratio among Japanese transsexuals is different than among Caucasians. PCOS and insulin resistance are common findings in FTM transsexual patients at initial presentation.


Use and impact of virtual primary care on quality and safety: The public's perspectives during the COVID-19 pandemic.
With the onset of Coronavirus disease (COVID-19), primary care has swiftly transitioned from face-to-face to virtual care, yet it remains largely unknown how this has impacted the quality and safety of care. We aim to evaluate patient use of virtual primary care models during COVID-19, including change in uptake, perceived impact on the quality and safety of care and willingness of future use. An online cross-sectional survey was administered to the public across the United Kingdom, Sweden, Italy and Germany. McNemar tests were conducted to test pre- and post-pandemic differences in uptake for each technology. One-way analysis of variance was conducted to examine patient experience ratings and perceived impacts on healthcare quality and safety across demographic characteristics. Respondents (n = 6326) reported an increased use of telephone consultations ( + 6.3%, p < .001), patient-initiated services ( + 1.5%, n = 98, p < 0.001), video consultations ( + 1.4%, p < .001), remote triage ( + 1.3, p < 0.001) and secure messaging systems ( + 0.9%, p = .019). Experience rates using virtual care technologies were higher for men (2.4 ± 1.0 vs. 2.3 ± 0.9, p < .001), those with higher literacy (2.8 ± 1.0 vs. 2.3 ± 0.9, p < .001), and participants from Germany (2.5 ± 0.9, p < .001). Healthcare timeliness and efficiency were the dimensions most often reported as being positively impacted by virtual technologies (60.2%, n = 2793 and 55.7%, n = 2,401, respectively), followed by effectiveness (46.5%, n = 1802), safety (45.5%, n = 1822), patient-centredness (45.2%, n = 45.2) and equity (42.9%, n = 1726). Interest in future use was highest for telephone consultations (55.9%), patient-initiated digital services (56.1%), secure messaging systems (43.4%), online triage (35.1%), video consultations (37.0%) and chat consultations (30.1%), although significant variation was observed between countries and patient characteristics. Future work must examine the drivers and determinants of positive experiences using remote care to co-create a supportive environment that ensures equitable adoption and use. Comparative analysis between countries and health systems offers the opportunity for policymakers to learn from best practices internationally.


Hepatoblastoma in families with polyposis coli.
We observed hepatoblastoma in four unrelated children who have a family history of polyposis coli and found this association in ten other kindreds in the literature. The one child in our series who has survived hepatoblastoma showed multiple colonic adenomas at 7 years of age. She and eight affected maternal relatives also had congenital hypertrophy of the retinal pigment epithelium, a new marker of gene carriers in some polyposis coli families. These findings suggest that childhood hepatoblastoma is an associated feature of familial polyposis coli.


Acute myeloid leukemia following solid organ transplantation: entity or novelty?
Due to the rarity of the disease, the characteristics of acute myeloid leukemia following solid organ transplantation (post-transplant AML; PT-AML) are unclear; furthermore, it is not known for certain whether PT-AML is a separate entity or not. We provide a systematic review of all previously reported cases of PT-AML in the English literature (n = 51). 45% of cases occurred after renal transplantation, and 72% were males. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr and a rapid decline in incidence after 5 yr. 26% of patients were asymptomatic at the time of presentation, and 42% were pancytopenic. M0/M1/M2, M3, M4/M5, and M6/M7 subtypes comprised 17%, 25%, 39%, and 19% of all cases, respectively. 36% of patients had unfavorable cytogenetic risk disease. The median overall survival was only 3 months. We observed several transplant-specific features: (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. (ii) All 4 cases of donor cell leukemia occurred after liver transplant. (iii) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients (P = 0.057). Our results suggest that PT-AML is a separate entity with distinct characteristics, which need to be investigated further in future research. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML.


Development of a field-friendly automated dietary assessment tool and nutrient database for India.
Studies of diet and disease risk in India and among other Asian-Indian populations are hindered by the need for a comprehensive dietary assessment tool to capture data on the wide variety of food and nutrient intakes across different regions and ethnic groups. The nutritional component of the India Health Study, a multicentre pilot cohort study, included 3908 men and women, aged 35-69 years, residing in three regions of India (New Delhi in the north, Mumbai in the west and Trivandrum in the south). We developed a computer-based, interviewer-administered dietary assessment software known as the 'NINA-DISH (New Interactive Nutrition Assistant - Diet in India Study of Health)', which consisted of four sections: (1) a diet history questionnaire with defined questions on frequency and portion size; (2) an open-ended section for each mealtime; (3) a food-preparer questionnaire; (4) a 24 h dietary recall. Using the preferred meal-based approach, frequency of intake and portion size were recorded and linked to a nutrient database that we developed and modified from a set of existing international databases containing data on Indian foods and recipes. The NINA-DISH software was designed to be easily adaptable and was well accepted by the interviewers and participants in the field. A predominant three-meal eating pattern emerged; however, patterns in the number of foods reported and the primary contributors to macro- and micronutrient intakes differed by region and demographic factors. The newly developed NINA-DISH software provides a much-needed tool for measuring diet and nutrient profiles across the diverse populations of India with the potential for application in other South Asian populations living throughout the world.


A comparison of the latencies of visually induced postural change and self-motion perception.
This study compared the latencies of visually induced postural change and self-motion perception under identical visual conditions. The results showed that a visual roll stimulus elicits postural tilt in the direction of scene motion and an increase in postural instability several seconds before the subject begins to perceive illusory self-motion (vection) in the opposite direction. Postural and vection latencies correlate highly with one another, but bear little relationship with the magnitude of either sway or vection.


Measuring hope during the COVID-19 outbreak in the Philippines: development and validation of the state locus-of-Hope scale short form in Filipino.
Various adaptations of the Dispositional Hope Scale have been validated and used for specific research and applied purposes. The Locus-of-Hope Scale was developed as a cultural adaptation that measures internal and external aspects of agency related to goal-pursuit that are typical in collectivist cultures. The scale has been used to account for variations in well-being-related factors in collectivist societies but still assumes that hope-related thoughts are dispositional. A State Locus-of-Hope Scale was developed to assess hope-related thinking concerning ongoing events and experience during the COVID-19 outbreak in the Philippines in March 2020. The 16-item scale in Filipino was adapted from a short version of Locus-of-Hope Scale. Using data from 3128 respondents, confirmatory factor analysis indicated a good fit between the four-factor model (compared to one-factor and two-factor models), supporting the scale's structural validity. There was also good evidence for the subscales' convergent and discriminant validity. Preliminary evidence for construct criterion validity was demonstrated by examining associations with well-being and anxiety. The results indicate the viability of the State Locus-of-Hope scale for assessing temporal hope-related thoughts that can inform efforts to understand how individuals engage in goal-related processes and maintain well-being in specific personal and social situations.


Sixth Daniel C. Baker, Jr. Memorial Lecture, Induction of cancer by DNA viruses.
The life cycles of the tumor virus SV40 and polyoma are discussed with particular emphasis on the role of the viral coded proteins which mediate the transformation of normal cells into their cancerous equivalents. One of more of these proteins possibly act by stimulating directly the synthesis of cellular DNA, while others may mimic the action of polypeptide mitogens that act at the cell surface.


[Restoration of ability to proliferate and produce mitogenic factor by human lymphocytes in a serum-free medium following their purification].
The response of purified and "non-purified" human blood lymphocytes to phytoheamagglutinin (PHA) and their capacity to produce mitogenic factor upon PHA-stimulation in protein-free and serum-containing culture medium were investigated. Non-purified lymphocytes lost the capacity to react to the stimulation with PHA and to produce the mitogenic factor in protein-free culture medium. Purification of lymphocytes on the density gradient or passing them through a column made them resume their response to PHA and their capacity to produce the mitogenic factor in protein-free medium. It is assumed that the inhibition of the response to PHA in protein-free culture medium may be caused by polymorphonuclear leucocytes.


Lipid transfer protein activities in type 1 diabetic patients without renal failure and nondiabetic control subjects and their association with coronary artery calcification.
This study examined the role of cholesteryl ester transfer (CET), cholesteryl ester transfer protein (CETP) activity, and phospholipid transfer protein (PLTP) activity in the increased prevalence of coronary artery calcification (CAC) in diabetic subjects compared with nondiabetic subjects and in the loss of the sex difference in CAC in diabetes. CETP activity, PLTP activity, and CET were measured in 195 type 1 diabetic subjects without renal failure and 194 nondiabetic control subjects of similar age (30-55 years) and sex distribution (50% female). CAC was quantified with electron beam computed tomography. CETP activity was higher in diabetic subjects (mean 84 arbitrary units [AU]) than in nondiabetic subjects (80 AU, P = 0.028). PLTP activity was also higher in diabetic subjects (96 AU) than in nondiabetic subjects (81 AU, P < 0.001). However, CET was lower in diabetic men (geometric mean 32 nmol. ml(-1).h(-1)) than nondiabetic men (37 nmol.ml(-1).h(-1), P = 0.004) and did not differ between diabetic (30 nmol. ml(-1).h(-1)) and nondiabetic (32 nmol.ml(-1).h(-1), P = 0.3) women. CETP and PLTP activities were not associated with CAC. CET was positively associated with CAC in both diabetic and nondiabetic subjects (odds ratio per 10 nmol.ml(-1).h(-1) increase in CET in all subjects = 1.4, P = 0.001). The prevalence of CAC was similar in diabetic (51%) and nondiabetic (54%, P = 0.7) men but was much higher in diabetic (47%) than nondiabetic (21%, odds ratio 3.6, P < 0.001) women so that there was no sex difference in CAC in diabetic subjects. The odds of CAC in diabetic women compared with nondiabetic women was altered little by adjustment for CETP activity, PLTP activity, or CET (odds ratio on adjustment 3.7, P < 0.001). The greater effect of diabetes on CAC in women than in men, i.e., the loss of the sex difference in CAC, was independent of CETP and PLTP activity and CET. In conclusion, among both diabetic and nondiabetic subjects, higher cholesteryl ester transfer is a risk factor for CAC. However, abnormalities in cholesteryl ester transfer or lipid transfer protein activities do not underlie the increased CAC risk in diabetic women compared with nondiabetic women or the loss of the sex difference in CAC in diabetes.


Treatment of experimental endocarditis caused by multidrug resistant Enterococcus faecium with ramoplanin and penicillin.
Antibiotic resistant strains of enterococci are being isolated with increasing frequency. Effective treatment of infections caused by Enterococcus faecium resistant to ampicillin, vancomycin and aminoglycosides has not been established. We studied the activity of ramoplanin, a new lipoglycopeptide antibiotic, against two strains of multidrug resistant E. faecium. In time kill studies, ramoplanin was bactericidal against both strains, but not in the presence of 50% serum. The combination of ramoplanin and penicillin was bactericidal even in the presence of serum. In rabbits with experimental endocarditis neither penicillin nor ramoplanin significantly reduced vegetation colony counts when given alone, although ramoplanin significantly reduced spleen and kidney bacterial counts of both strains. The combination of ramoplanin plus penicillin resulted in a significant reduction of vegetation bacterial counts (-3.2 and -3.7 log10 cfu/g for strains VA3 and MMC3, respectively, P < 0.01). All spleen cultures and 9 out of 10 kidney cultures from each strain were sterile following combination therapy. While ramoplanin will not be available for parenteral therapy, further research into the development of other lipoglycopeptide antibiotics is warranted.


Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients.
Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode.


Busulfan conjugation by glutathione S-transferases alpha, mu, and pi.
Busulfan is eliminated by glutathione S-transferase (GST)-catalyzed conjugation with glutathione (GSH). We have characterized the busulfan-conjugating activity of purified human liver GSTA1-1, GSTA1-2, GSTA2-2, GSTM1-1, and placental GSTP1-1. Isoforms were purified from cytosol by GSH-affinity chromatography and chromatofocusing. In addition, the busulfan-conjugating activity of cDNA-expressed GTH1 and GTH2, corresponding to GSTA1-1 and GSTA2-2, were characterized. The major product of busulfan conjugation, a thiophenium ion (THT+), was assayed by GC/MS after conversion to tetrahydrothiophene (THT). THT+ formation rate increased linearly with busulfan concentration up to its solubility limit for all GST isoforms. Because Vmax and KM could not be determined separately, the slope of the velocity vs. substrate concentration plot, Vmax/KM was used to compare isoform activities. Vmax/KM for GSTA1-1 was 7.95 microliters/min/mg protein, the highest busulfan-conjugating activity of all human liver and placenta isoforms evaluated. GSTM1-1 and GSTP1-1, respectively, had 46% and 18% of the activity of GSTA1-1. Since the polymorphic mu-class GST catalyzed busulfan conjugation, we examined busulfan clearance in 50 patients undergoing high-dose busulfan before bone marrow transplantation. Busulfan clearance was normally distributed, suggesting that GSTM1-1 does not contribute significantly to the elimination of busulfan from the body. We conclude that GSTA1-1 is the major isoform catalyzing busulfan conjugation, whereas GSTM1-1 and GSTP1-1 may be important in the protection of specific cells.


International variation in prostate cancer incidence and mortality rates.
Wide variation exists internationally for prostate cancer (PCa) rates due to differences in detection practices, treatment, and lifestyle and genetic factors. We present contemporary variations in PCa incidence and mortality patterns across five continents using the most recent data from the International Agency for Research on Cancer. PCa incidence and mortality estimates for 2008 from GLOBOCAN are presented. We also examine recent trends in PCa incidence rates for 40 countries and mortality rates for 53 countries from 1985 and onward via join-point analyses using an augmented version of Cancer Incidence in Five Continents and the World Health Organization mortality database. Estimated PCa incidence rates remain most elevated in the highest resource counties worldwide including North America, Oceania, and western and northern Europe. Mortality rates tend to be higher in less developed regions of the world including parts of South America, the Caribbean, and sub-Saharan Africa. Increasing PCa incidence rates during the most recent decade were observed in 32 of the 40 countries examined, whereas trends tended to stabilize in 8 countries. In contrast, PCa mortality rates decreased in 27 of the 53 countries under study, whereas rates increased in 16 and remained stable in 10 countries. PCa incidence rates increased in nearly all countries considered in this analysis except in a few high-income countries. In contrast, the increase in PCa mortality rates mainly occurred in lower resource settings, with declines largely confined to high-resource countries.


Outcomes of Minority COVID-19 patients managed with ECMO: A single-center experience.
The coronavirus disease 2019 (COVID-19) pandemic has significantly burdened the global healthcare system since December 2019. Minority populations are found to have a higher incidence of hospitalization and higher mortality when compared to Caucasians. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure refractory to conventional management. To our knowledge, no data has been reported on outcome differences between Minority COVID-19 patients and Caucasian COVID-19 patients managed with ECMO. We aimed to investigate the outcome differences between these two groups. Our retrospective cohort study had 23 adults (aged 18 and older) diagnosed with COVID-19 by polymerase chain reaction. All patients developed acute respiratory distress syndrome (ARDS), refractory to conventional treatment, and were managed on ECMO support. The primary outcome of interest was mortality; the secondary outcome was the rate of ECMO-related complications. The overall mortality rate of our study was higher (70%) than other reports of the COVID-19 population on ECMO. Caucasians in our study had more severe respiratory acidosis with carbon dioxide retention and appeared to have a higher mortality rate of 85.7% compared to Minorities (62.5%). No differences in complication rates between these two groups were identified. Our cohort revealed a high overall mortality rate of COVID-19 patients on ECMO support. The Caucasian group was observed to have higher mortality than the Minority group. The high overall mortality was likely attributed to the Caucasian group, which had more severe respiratory acidosis before ECMO initiation, a known predictor of poor prognosis in ARDS patients. Our cohort's ethnic composition may also partially explain the high mortality rate since COVID-19 Minorities are reported to have worse outcomes than Caucasians. Larger and randomized studies are needed to investigate further the mortality and complication differences between Minority and Caucasian patients diagnosed with COVID-19 and managed by ECMO.


Protocol update and preliminary results of EACVI/HFA Cardiac Oncology Toxicity (COT) Registry of the European Society of Cardiology.
European Association of Cardiovascular Imaging/Heart Failure Association Cardiac Oncology Toxicity Registry was launched in October 2014 as a European Society of Cardiology multicentre registry of breast cancer patients referred to imaging laboratories for routine surveillance, suspected, or confirmed anticancer drug-related cardiotoxicity (ADRC). After a pilot phase (1 year recruitment and 1 year follow-up), some changes have been made to the protocol (version 1.0) and electronic case report form. Main changes of the version 2.0 concerned exclusion criteria, registry duration, and clarification of the population characteristics. Breast cancer radiotherapy has been removed as an exclusion criterion, which involves now only history of a pre-chemotherapy left ventricular dysfunction. The period for long-term registry recruitment has been reduced (December 2017), but the target study population was extended to 3000 patients. The characteristics of the population are now better defined: patients seen in an imaging lab, which will include patients undergoing chemotherapy with associated targeted therapy or no targeted therapy, at increased risk of ADRC. In total, 1294 breast cancer patients have been enrolled, and 783 case report forms locked from October 2014 to November 2016. Of these, 481 (61.4%) were seen at first evaluation and 302 (38.6%) while on oncologic treatment with anticancer drugs. Fifty-two patients (17.2%) were not in targeted therapies, 191 (63.3%) were ongoing targeted therapy, and 59 (19.5%) had completed it. Twenty-three (2.9%) patients had a suspected diagnosis and 35 (4.5%) a confirmed diagnosis of ADRC. Arterial hypertension was the most prevalent cardiovascular risk factor (29.2%) followed by diabetes (6.1%). Previous history of heart failure accounted for 0.5%, whereas previous cardiac disease was identified in 6.3% of population. The changes of the original protocol of the COT Registry and first update allow a first glance to the panorama of cardiovascular characteristics of breast cancer patients enrolled.


Methylammonium-Based Quasi-Two-Dimensional Perovskite Single Crystals for Highly Sensitive X-ray Detection and Imaging.
The strategy of introducing large organic cations into three-dimensional perovskites could reduce the dimensionality of perovskites to form quasi-two-dimensional (quasi-2D) perovskites, resulting in increased stability and reduced detection limits due to less ion migration. Herein, a quasi-2D perovskite single crystal (BDA)(MA)2Pb3Br10 (BDA = NH3C4H8NH3, MA = CH3NH3) with a layered structure was grown by the temperature-cooling solution method. The X-ray detector based on the (BDA)(MA)2Pb3Br10 single crystal has a sensitivity as high as 1984 μC Gy-1 cm-2 at 55.6 V/mm, and it could detect X-rays as low as 28.12 nGy s-1 at 22.2 V/mm. In addition, the X-ray imaging system based on the single-crystal device easily distinguishes between metals and plastics and exhibits a spatial resolution estimated as 250 μm, indicating the feasibility of (BDA)(MA)2Pb3Br10 crystals for X-ray imaging. This research offers a method for the design of quasi-2D layered perovskites and enhances photoelectronic applications in X-ray inspection and imaging.


Conventional and whitening toothpastes: cytotoxicity, genotoxicity and effect on the enamel surface.
To evaluate the cytotoxicity and genotoxicity of whitening and common toothpastes, and the surface roughness of tooth enamel submitted to brushing with both toothpastes. Samples of whitening toothpastes [Colgate Whitening (CW) and Oral-B Whitening (OBW)] and regular (non-whitening) toothpastes (Colgate and Oral-B) were extracted in culture medium. Gingival human fibroblasts (FMM-1) were placed in contact with different dilutions of culture media that had been previously exposed to such materials, and the cytotoxicity was evaluated using the MTT assay. The genotoxicity was assessed by the micronucleus formation assay in Chinese hamster fibroblasts (V79). The cell survival rate and micronuclei number were assessed before and after exposure to the toothpaste extracts. For the surface roughness evaluation, 20 bovine tooth specimens, divided into four groups according to toothpastes, were submitted to 10,000 brushing cycles. The results were analyzed using the Mann-Whitney U and two-way ANOVA tests (P < 0.05). MTT assay showed that Colgate was significantly less cytotoxic than CW, Oral-B and OBW at all dilutions (P < 0.01). CW was the most cytotoxic toothpaste (P < 0.01). The whitening toothpastes showed the highest numbers of micronuclei compared to the untreated control (UC) (P < 0.01). Colgate and Oral-B toothpastes were not genotoxic compared to UC (P = 0.326). The OBW toothpaste was statistically significantly abrasive to the enamel surface (P < 0.01). The whitening toothpastes and Oral-B were cytotoxic to the cells. The whitening toothpastes were more genotoxic to cells in vitro than the common toothpastes, and genotoxicity was more pronounced in the OBW toothpaste.


Macular hole following Bartonella henselae neuroretinitis.
To report a case of macular hole secondary to Bartonella henselae neuroretinitis. Observational case report. An 11 year-old boy presented urgently with a decrease of visual acuity in the left eye. Posterior segment examination revealed neuroretinitis attributed to Bartonella henselae. Treatment was initiated, resulting in the disappearance of symptoms. Follow-up consultations 7 months later showed a further decline in visual acuity secondary to a macular hole. Cat scratch disease is a rare pathology and is most often considered benign. Serious complications can nonetheless occur, such as neuroretinitis, choroidal nodules, and disciform keratitis. The authors report a case of sequellar macular hole. They found only one previous report of macular hole caused by B henselae, which, contrary to their case, appeared rapidly 12 days after presentation.


Apnoeic oxygenation during neonatal intubation.
'Apnoeic oxygenation' describes the diffusion of oxygen across the alveolar-capillary interface in the absence of tidal respiration. Apnoeic oxygenation requires a patent airway, the diffusion of oxygen to the alveoli, and cardiopulmonary circulation. Apnoeic oxygenation has varied applications in adult medicine including facilitating tubeless anaesthesia or improving oxygenation when a difficult airway is known or anticipated. In the paediatric population, apnoeic oxygenation prolongs the time to oxygen desaturation, facilitating intubation. This application has gained attention in neonatal intensive care where intubation remains a challenging procedure. Difficulties are related to the infant's size and decreased respiratory reserve. In addition, policy changes have led to limited opportunities for operators to gain proficiency. Until recently, evidence of benefit of apnoeic oxygenation in the neonatal population came from a small number of infants recruited to paediatric studies. Evidence specific to neonates is emerging and suggests apnoeic oxygenation may increase intubation success and limit physiological instability during the procedure. The best way to deliver oxygen to facilitate apnoeic oxygenation remains an important question.


Mobility of P elements in drosophilids and nondrosophilids.
The mobility properties of the Drosophila melanogaster P element in drosophilid and nondrosophilid species has been determined using a P-element mobility assay that is conducted transiently in insect embryos. P elements are mobilizable in all drosophilids tested, including species outside the genus Drosophila but not in the related Tephritidae (order: Diptera), although the P-element gene necessary for mobility, transposase, is transcribed. These results show that without modifications P elements will not serve as general insect gene vectors and suggest that nonconserved host-encoded factors participate in the transposition of P elements. Our methods will be generally useful for analyzing the cis- and trans-acting factors required for P-element mobility in vivo and could be used to analyze the mobility properties of other transposable elements in insects.


JESS, a joint expert speciation system--V: approaching thermodynamic property prediction for multicomponent concentrated aqueous electrolyte solutions.
Considerable difficulties persist in modelling the thermodynamics of multicomponent aqueous electrolyte solutions, especially at high concentrations. The widely adopted Pitzer formalism suffers from severe disadvantages, particularly with the combinatorial increase in mixing parameters required in multicomponent systems. As an alternative, the simple mixing rules of Young, of Harned and of Zdanovskii have been employed to predict the properties of mixtures using only the properties of the binary constituents with few or no additional parameters. Among these, Zdanovskii's rule is particularly promising because it constitutes a fundamental criterion for ideal mixing, i.e. when solutions having the same solvent activity are mixed in any proportion, the solvent activity remains unchanged. Many mixtures of strong electrolyte solutions are known from experiment to obey Zdanovskii's rule. This is important because application to aqueous electrolyte systems of practical interest has been hindered due to the process-intensive determination of water activities using the Gibbs-Duhem relation. This paper describes an alternative method which efficiently calculates the water activity of a multicomponent solution obeying Zdanovskii's rule. Some specific examples of the method are presented and various applications considered. In some systems, where deviations from Zdanovskii's rule occur, a single empirical parameter can be obtained and can be easily incorporated into the calculations.


Global modeling of transcriptional responses in interaction networks.
Cell-biological processes are regulated through a complex network of interactions between genes and their products. The processes, their activating conditions and the associated transcriptional responses are often unknown. Organism-wide modeling of network activation can reveal unique and shared mechanisms between tissues, and potentially as yet unknown processes. The same method can also be applied to cell-biological conditions in one or more tissues. We introduce a novel approach for organism-wide discovery and analysis of transcriptional responses in interaction networks. The method searches for local, connected regions in a network that exhibit coordinated transcriptional response in a subset of tissues. Known interactions between genes are used to limit the search space and to guide the analysis. Validation on a human pathway network reveals physiologically coherent responses, functional relatedness between tissues and coordinated, context-specific regulation of the genes. Implementation is freely available in R and Matlab at http://www.cis.hut.fi/projects/mi/software/NetResponse


Stochastic accumulation of feature information in perception and memory.
It is now well established that the time course of perceptual processing influences the first second or so of performance in a wide variety of cognitive tasks. Over the last 20 years, there has been a shift from modeling the speed at which a display is processed, to modeling the speed at which different features of the display are perceived and formalizing how this perceptual information is used in decision making. The first of these models (Lamberts, 1995) was implemented to fit the time course of performance in a speeded perceptual categorization task and assumed a simple stochastic accumulation of feature information. Subsequently, similar approaches have been used to model performance in a range of cognitive tasks including identification, absolute identification, perceptual matching, recognition, visual search, and word processing, again assuming a simple stochastic accumulation of feature information from both the stimulus and representations held in memory. These models are typically fit to data from signal-to-respond experiments whereby the effects of stimulus exposure duration on performance are examined, but response times (RTs) and RT distributions have also been modeled. In this article, we review this approach and explore the insights it has provided about the interplay between perceptual processing, memory retrieval, and decision making in a variety of tasks. In so doing, we highlight how such approaches can continue to usefully contribute to our understanding of cognition.


Finite Element Study on Continuous Rotating versus Reciprocating Nickel-Titanium Instruments.
In the present study, GTX and ProTaper as continuous rotating endodontic files were numerically compared with WaveOne reciprocating file using finite element analysis, aiming at having a low cost, accurate/trustworthy comparison as well as finding out the effect of instrument design and manufacturing material on its lifespan. Two 3D finite element models were especially prepared for this comparison. Commercial engineering CAD/CAM package was used to model full detailed flute geometries of the instruments. Multi-linear materials were defined in analysis by using real strain-stress data of NiTi and M-Wire. Non-linear static analysis was performed to simulate the instrument inside root canal at a 45° angle in the apical portion and subjected to 0.3 N.cm torsion. The three simulations in this study showed that M-Wire is slightly more resistant to failure than conventional NiTi. On the other hand, both materials are fairly similar in case of severe locking conditions. For the same instrument geometry, M-Wire instruments may have longer lifespan than the conventional NiTi ones. In case of severe locking conditions both materials will fail similarly. Larger cross sectional area (function of instrument taper) resisted better to failure than the smaller ones, while the cross sectional shape and its cutting angles could affect instrument cutting efficiency.


High-Performance WSe2 Complementary Metal Oxide Semiconductor Technology and Integrated Circuits.
Because of their extraordinary structural and electrical properties, two-dimensional materials are currently being pursued for applications such as thin-film transistors and integrated circuit. One of the main challenges that still needs to be overcome for these applications is the fabrication of air-stable transistors with industry-compatible complementary metal oxide semiconductor (CMOS) technology. In this work, we experimentally demonstrate a novel high performance air-stable WSe2 CMOS technology with almost ideal voltage transfer characteristic, full logic swing and high noise margin with different supply voltages. More importantly, the inverter shows large voltage gain (∼38) and small static power (picowatts), paving the way for low power electronic system in 2D materials.


De-regulated expression of the BRG1 chromatin remodeling factor in bone marrow mesenchymal stromal cells induces senescence associated with the silencing of NANOG and changes in the levels of chromatin proteins.
Stem cells have a peculiar chromatin architecture that contributes to their unique properties, including uncommitted status, multi/pluripotency and self-renewal. We analyzed the effect of the de-regulation of the SWI/SNF chromatin remodeling complex in mesenchymal stromal cells (MSC) through the silencing and up-regulation of BRG1, which is the ATPase subunit of the complex. The altered expression of BRG1 promoted the senescence of MSC with suppression of the NANOG transcription, which is part of the transcriptional circuitry governing stem cell functions. To gain insight on the way NANOG was silenced, we evaluated how the de-regulated BRG1 expression affect the binding of activators and repressors on the NANOG promoter. We found 4 E2F binding motifs on NANOG promoter, which can be occupied by RB1 and RB2/P130. These are members of the retinoblastoma gene family. In MSC with a silenced BRG1, the relative binding of the 2 retinoblastoma proteins increased, and this was associated with the recruitment of DNMT1. This induced the methylation of CpG on the NANOG promoter. Opposingly, when a high level of BRG1 was present, the same E2F binding motifs were docking sites for BRG1, which induced chromatin compaction without CpG methylation but with increased histone deacetylation, associated with the presence of HDAC1 on E2F binding sites. Besides the sharp regulation of the NANOG expression, we evidenced, through proteomic analysis, that the de-regulation of the SWI/SNF function affected the expression of histones and other nuclear proteins involved in "nuclear architecture," suggesting that BRG1 may act as global regulator of gene expression.


A simulation system for craniofacial surgeries based on 3D image processing.
A practical simulation system based on analysis of clinical surgical procedures is described. The system provides fundamental manipulation operations to simulate actual surgical activities. There is a simulated cutting operation for sectioning a bone into various arbitrary shapes, a movement operation to transport a bone block to a desired position, and a restricted-movement operation to move a bone block until it comes into contact with other bone. The system also generates a skin surface image of a postoperative patient based on a simulated plan of bone manipulation. An operational system to enable physicians handling the system to work at ease has been devised. The structure and function of the system are described, and examples of its use in simulation are given.


MSACompro: protein multiple sequence alignment using predicted secondary structure, solvent accessibility, and residue-residue contacts.
Multiple Sequence Alignment (MSA) is a basic tool for bioinformatics research and analysis. It has been used essentially in almost all bioinformatics tasks such as protein structure modeling, gene and protein function prediction, DNA motif recognition, and phylogenetic analysis. Therefore, improving the accuracy of multiple sequence alignment is important for advancing many bioinformatics fields. We designed and developed a new method, MSACompro, to synergistically incorporate predicted secondary structure, relative solvent accessibility, and residue-residue contact information into the currently most accurate posterior probability-based MSA methods to improve the accuracy of multiple sequence alignments. The method is different from the multiple sequence alignment methods (e.g. 3D-Coffee) that use the tertiary structure information of some sequences since the structural information of our method is fully predicted from sequences. To the best of our knowledge, applying predicted relative solvent accessibility and contact map to multiple sequence alignment is novel. The rigorous benchmarking of our method to the standard benchmarks (i.e. BAliBASE, SABmark and OXBENCH) clearly demonstrated that incorporating predicted protein structural information improves the multiple sequence alignment accuracy over the leading multiple protein sequence alignment tools without using this information, such as MSAProbs, ProbCons, Probalign, T-coffee, MAFFT and MUSCLE. And the performance of the method is comparable to the state-of-the-art method PROMALS of using structural features and additional homologous sequences by slightly lower scores. MSACompro is an efficient and reliable multiple protein sequence alignment tool that can effectively incorporate predicted protein structural information into multiple sequence alignment. The software is available at http://sysbio.rnet.missouri.edu/multicom_toolbox/.


Assessing Mode-Switching Strategies for Assistive Robotic Manipulators Using a Preliminary Version of the Novel Non-invasive Tongue-Computer Interface.
The inductive tongue-computer interface allows individuals with tetraplegia to control assistive devices. However, controlling assistive robotic arms often requires more than 14 different commands, which cannot always fit into a single control layout. Previous studies have separated the commands into modes, but few have investigated strategies to switch between them. In this feasibility study, we compare the efficiency of switching modes using buttons, swipe gestures and double taps using a preliminary version of a new non-invasive mouthpiece unit (nMPU), which includes an integrated activation unit and a single sensor board. Three participants controlled a JACO assistive robot to pick up a bottle using different mode-switching strategies. Compared with switching modes with buttons, switching modes with swipes and double taps increased the task completion time by 21% and 58% respectively. Therefore, we recommend that configurations with multiple modes for the non-invasive tongue-computer interface include buttons for mode-switching.Clinical relevance- Cumbersome mode-switching strategies can lower a control interface's responsiveness and contribute to end-user abandonment of assistive technologies. This study showed that using buttons to switch modes is more reliable. Moreover, this study will inform the development of future control layouts with improved usability.


The role of hepatic invariant NKT cells in systemic/local inflammation and mortality during polymicrobial septic shock.
NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jalpha18(-/-)) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3(+)alpha-galactosylceramide CD1d tetramer(+) cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.


Can research participants comment authoritatively on the validity of their self-reports of mind wandering and task engagement?
The study of mind wandering rests upon the assumption that people are able to consistently and accurately introspect and report on these sorts of mental experiences. Although there is some initial evidence that people can indeed accurately report on the subjective experience of mind wandering, to date, no work has directly examined people's degree of confidence in their self-reports of mind wandering and the effects that confidence has on the accuracy of such reports. In the present study, participants completed a sustained-attention task during which they intermittently provided assessments of task engagement (i.e., whether they were focused on the task or mind wandering), as well as reports of confidence in the accuracy of their assessments. This study yielded 3 key findings: We found substantial between- and within-subject variability in both (a) reported mind wandering and (b) confidence in mind-wandering reports, and, most critically, (c) we found that the relation of reported mind wandering and task performance varied as a function of confidence. We discuss the implications of these findings in the context of the literature on mind wandering.


MAIT cell recognition of MR1 on bacterially infected and uninfected cells.
Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surface of APCs cultured both with and without bacteria, we undertook extensive mutational analysis of both the MAIT TCR and MR1 molecule. We found differential contribution of particular amino acids to the MAIT TCR-MR1 interaction based upon the presence of bacteria, supporting the hypothesis that the structure of the MR1 molecules with the microbial-derived ligand(s) differs from the one with the endogenous ligand(s). Furthermore, we demonstrate that microbial-derived ligand(s) is resistant to proteinase K digestion and does not extract with common lipids, suggesting an unexpected class of antigen(s) might be recognized by this unique lymphocyte population.


Should styrene be sampled on the left or right shoulder?--An important question in employee self-assessment.
A self-operated personal sampling technique called 'self assessment of exposure' (SAE) has been suggested as an easy method for collecting inhalation exposure data, as the workers themselves are performing the sampling. Employers and employees have raised the question of whether a different estimate of the air concentration is likely to be obtained depending on whether the sampler is fastened at the left or the right shoulder. In order to answer this question, the exposure to styrene vapour in two different small enterprises within the reinforced plastics industry was measured. Seven workers participated and the air sampling was performed by diffusive sampling. We observed no statistically significant difference in the determined air concentration of styrene between the left and right shoulder (P = 0.878). The results strongly indicate that the fastening of a sampler on the left or right shoulder does not produce a difference in the estimation of the inhalation exposure. SAE can thus be used to collect reliable exposure data of styrene vapour. The reliability of SAE will most certainly inspire occupational hygienists, physicians and other experts to involve the workers in repeated exposure measurements. Taking the exposure variability into account, repeated measurements are crucial when evaluating acute and chronic health effects following inhalation exposure to gases and vapours from chemical hazards.


Hughlings Jackson's Dr Z: the paradigm of temporal lobe epilepsy revealed.
On 10 January 1894, a distinguished physician died in London of an overdose of chloral hydrate. The event was of vital interest to Hughlings Jackson who attended the post-mortem examination with a bevy of witnesses. He begged his colleague Walter Colman "to search the taste region of Ferrier on each half of the brain very carefully." They were rewarded by finding " a very small focus of softening in that region (in the uncinate gyrus) of the left half of the brain." Jackson had thus discovered the most discrete and circumscribed lesion of the temporal lobe yet described to assoicate with the most detailed and elegant self report of psychomotor epilepsy yet published. For the physician, whom Jackson and Colman called "Dr Z" in their report in Brain(2) had been Jackson's patient since 1877 and his own account of his epileptic experience had occupied six pages of Jackson's 1888 article "On a particular variety of epilepsy...."(7) Jackson had himself witnessed several of Dr Z's attacks. The case enabled Jackson to argue that the complex symptomatology of the seizure was due to "reflex" effects of epileptic discharges in that area of brain. It is the paradigm of temporal lobe epilepsy.


Sources, fate, and toxic hazards of oxygenated polycyclic aromatic hydrocarbons (PAHs) at PAH-contaminated sites.
In this paper we show that oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are important cocontaminants that should be taken into account during risk assessment and remediation of sites with high levels of PAHs. The presented data, which have been collected both from our own research and the published literature, demonstrate that oxy-PAHs are abundant but neglected contaminants at these sites. The oxy-PAHs show relatively high persistency and because they are formed through transformation of PAHs, their concentrations in the environment may even increase as the sites are remediated by methods that promote PAH degradation. Furthermore, we show that oxy-PAHs are toxic to both humans and the environment, although the toxicity seems to be manifested through other effects than those known to be important for polycyclic aromatic compounds in general, that is, mutagenicity and carcinogenicity. Finally, we present data that support the hypothesis that oxy-PAHs are more mobile in the environment than PAHs, due to their polarity, and thus have a higher tendency to spread from contaminated sites via surface water and groundwater. We believe that oxy-PAHs should be included in monitoring programs at PAH-contaminated sites, even if a number of other toxicologically relevant compounds that may also be present, such as nitro-PAHs and azaarenes, are not monitored. This is because oxy-PAH levels are difficult to predict from the PAH levels, because their environmental behavior differs substantially from that of PAHs, and oxy-PAHs may be formed as PAHs are degraded.


Heat shock factor 2 is activated during mouse heart development.
Two members of the heat shock transcription factor family, HSF1 and HSF2, have been identified as activators of mammalian heat shock gene expression. HSF1 acts as a classical stress-responsive factor, whereas HSF2 might play a role in embryogenesis, since it is active during pre- and post-implantation periods up to 15.5 days of mouse embryonic development. In this study, we analyzed HSF1 and HSF2 expression and activation during mouse heart formation. Our results show an abundant expression of HSF1 throughout heart development. In contrast, expression of the alternatively spliced HSF2-alpha and HSF2-beta, and an additional higher molecular weight isoform is strongly upregulated in the developing mouse heart at E11.5-12.5, a stage after which tubular heart has looped and chambers formed, and the myocardial walls are maturating and the valves differentiating. At the same developmental stage, HSF2 DNA-binding activity is transiently induced, whereas the weak HSE-binding activity, which is detected throughout heart development, consists primarily of HSF1. Interestingly, heat shock gene expression shows no temporal or spatial correlation with HSF2 expression and activation. Taken together, our results indicate that HSF2 activation is associated with specific stages of heart formation but is not involved in the regulation of inducible heat shock gene expression.


Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking.
Cells require growth factors to support glucose metabolism for survival and growth. It is unclear, however, how noninsulin growth factors may regulate glucose uptake and glucose transporters. We show that the hematopoietic growth factor interleukin (IL)3, maintained the glucose transporter Glut1 on the cell surface and promoted Rab11a-dependent recycling of intracellular Glut1. IL3 required phosphatidylinositol-3 kinase activity to regulate Glut1 trafficking, and activated Akt was sufficient to maintain glucose uptake and surface Glut1 in the absence of IL3. To determine how Akt may regulate Glut1, we analyzed the role of Akt activation of mammalian target of rapamycin (mTOR)/regulatory associated protein of mTOR (RAPTOR) and inhibition of glycogen synthase kinase (GSK)3. Although Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt-stimulated mTOR/RAPTOR may promote Glut1 transporter activity. In contrast, inhibition of GSK3 did not affect Glut1 internalization but nevertheless maintained surface Glut1 levels in IL3-deprived cells, possibly via enhanced recycling of internalized Glut1. In addition, Akt attenuated Glut1 internalization through a GSK3-independent mechanism. These data demonstrate that intracellular trafficking of Glut1 is a regulated component of growth factor-stimulated glucose uptake and that Akt can promote Glut1 activity and recycling as well as prevent Glut1 internalization.


Adult community acquired bacterial meningitis in a Singaporean teaching hospital. A seven-year overview (1993-2000).
The objective of this study is to describe the bacteriological, clinical and laboratory features of community acquired bacterial meningitis in adults admitted to a Singapore tertiary-care hospital. Two hundred sixty-nine cases of meningitis or meningoencephalitis admitted between 1993 and 2000 were identified by their discharge diagnosis codes. All case records except for 57 which could not be retrieved were retrospectively reviewed. Patients less than 14 years or with skull fractures, post-neurosurgery or with indwelling intracranial devices were excluded. Inclusion criteria was a clinical picture compatible with a diagnosis of bacterial meningitis with either (1) positive cerebral-spinal fluid (CSF) cultures or latex coagglutination or CSF neutrophilic pleocytosis accompanied by positive blood cultures or (2) in the absence of positive blood cultures, CSF cultures and latex agglutination, presence of CSF pleocytosis of at least 100 neutrophils per microL. Fifteen "culture-positive" and 11 "culture negative" cases were identified. Six (55%) of the "culture-negative" cases received antibiotics prior to admission. Cultures grew Streptococcus pneumoniae in four cases, three cases each of Group B streptococci and Neisseria meningitides. Listeria monocytogenes and Klebsiella pneumoniae were each seen twice and Streptococcus suis once. All cases of Group B streptococci occurred in the year 1998. Mortality was 19% (n = 5), six developed infections in other sites, three epileptic seizures, three developed hydrocephalus, and two hearing loss. Pathogens are similar to those reported in other studies but for an outbreak of Group B Streptococcus in 1998. There were a high number of "culture-negative" cases which may be due to preceding antibiotic intervention.


Coronary sinus obstruction by primary cardiac lymphoma as a cause of dyspnea due to significant diastolic dysfunction and elevated filling pressures.
A 52-year-old woman presented with severe dyspnea of 2 weeks' duration. Echocardiography showed an enlarged left atrium but normal global left ventricular systolic function. However, a huge, irregularly shaped mass at the dilated coronary sinus that extended into the right atrium was noted. Mitral inflow showed restrictive physiology and the E/E' ratio was significantly elevated, suggesting elevated left ventricular filling pressures. Echocardiography-guided biopsy was performed, and a diagnosis of primary cardiac lymphoma (diffuse large B-cell type) was made. After the first cycle of chemotherapy, the patient's symptom was markedly improved. A follow-up echocardiogram showed complete removal of the mass and a change in left ventricular filling pattern from restrictive to relaxation abnormality with decreased E/E'. The present case demonstrates a rare cause of diastolic dysfunction due to coronary sinus obstruction by tumor infiltration. Diastolic dysfunction caused by coronary sinus obstruction was improved after the tumor was resolved by chemotherapy.


Future Earth Health Knowledge-Action Network.
Future Earth is an international research platform providing the knowledge and support to accelerate our transformations to a sustainable world. Future Earth 2025 Vision identified eight key focal challenges, and challenge #6 is to "Improve human health by elucidating, and finding responses to, the complex interactions amongst environmental change, pollution, pathogens, disease vectors, ecosystem services, and people's livelihoods, nutrition and well-being." Several studies, including the Rockefeller Foundation/Lancet Planetary Health Commission Report of 2015, the World Health Organization/Convention on Biological Diversity report and those by oneHEALTH (former ecoHEALTH), have been conducted over the last 30 years. Knowledge-Action Networks (KANs) are the frameworks to apply Future Earth principles of research to related activities that respond to societal challenges. Future Earth Health Knowledge-Action Network will connect health researchers with other natural and social scientists, health and environmental policy professionals and leaders in government, the private sector and civil society to provide research-based solutions based on better, integrated understanding of the complex interactions between a changing global environment and human health. It will build regional capacity to enhance resilience, protect the environment and avert serious threats to health and will also contribute to achieving Sustainable Development Goals. In addition to the initial partners, Future Earth Health Knowledge-Action Network will further nourish collaboration with other on-going, leading research programmes outside Future Earth, by encouraging them in active participation.


National campaigns to improve antibiotic use.
High levels of antibiotic consumption are driving levels of bacterial resistance that threaten public health. Nonetheless, antibiotics still provide highly effective treatments for common diseases with important implications for human health. The challenge for public education is to achieve a meaningful reduction in unnecessary antibiotic use without adversely affecting the management of bacterial infections. This paper focuses on the lessons learned from national campaigns in countries (Belgium and France) with high antibiotic use. Evaluation of these national campaigns showed the importance of television advertising as a powerful medium to change attitudes and perhaps also behaviour with regard to antibiotics. Moreover, in both countries, strong evidence suggested reduced antibiotic prescribing. However, adverse effects associated with a reduction in antibiotic prescribing were not monitored. We conclude that carefully designed mass education campaigns could improve antibiotic use nationally and should be considered in countries with high antibiotic use. However, these campaigns should employ techniques of social marketing and use appropriate outcome measures. The benefits and risks of such campaigns have been less well established in countries where antibiotic use is already low or declining.


Differential expression of metallothionein isoforms in terrestrial snail embryos reflects early life stage adaptation to metal stress.
The aim of this study was to analyze the expression of three metallothionein (MT) isoform genes (CdMT, CuMT and Cd/CuMT), already known from adults, in the Early Life Stage (ELS) of Cantareus aspersus. This was accomplished by detection of the MT isoform-specific transcription adopting Polymerase Chain Reaction (PCR) amplification and quantitative Real Time (qRT)-PCR of the three MT genes. Freshly laid eggs were kept for 24 hours under control conditions or exposed to three cadmium (Cd) solutions of increasing concentration (5, 10, and 15 mg Cd/L). The transcription of the three MT isoform genes was detected via PCR in 1, 6 and 12-day-old control or Cd-exposed embryos. Moreover, the transcription of this isoform genes during development was followed by qRT-PCR in 6 and 12-day-old embryos. Our results showed that the CdMT and Cd/CuMT genes, but not the CuMT gene, are expressed in embryos at the first day of development. The transcription of the 3 MT genes in control embryos increased with development time, suggesting that the capacities of metal regulation and detoxification may have gradually increased throughout embryogenesis. However in control embryos, the most highly expressed MT gene was that of the Cd/CuMT isoform, whose transcription levels greatly exceeded those of the other two MT genes. This contrasts with the minor significance of this gene in adult snails and suggests that in embryos, this isoform may play a comparatively more important role in metal physiology compared to adult individuals. This function in adult snails appears not to be related to Cd detoxification. Instead, snail embryos responded to Cd exposure by over-expression of the CdMT gene in a concentration-dependent manner, whereas the expression of the Cd/CuMT gene remained unaffected. Moreover, our study demonstrates the ability of snail embryos to respond very early to Cd exposure by up-regulation of the CdMT gene.


Engorgement of Deep Medullary Veins in Neurosarcoidosis: A Common-Yet-Underrecognized Cerebrovascular Finding on SWI.
We describe the prevalence and potential significance of deep medullary vein engorgement on SWI in patients with neurosarcoidosis, a finding that has not been described previously. Engorgement was evaluated for possible associations with meningeal or perivascular disease, intracranial hemorrhage, and venous thrombosis, as well as with modified Rankin Scale scores at the time of MR imaging and at follow-up. Deep medullary vein engorgement was seen in 7 of 21 patients and was more common in men. Patients with venous engorgement had a significantly increased incidence of microhemorrhages, perivascular disease, and hydrocephalus. There was no association with the degree of leptomeningeal disease, venous dural sinus thrombosis, or modified Rankin Scale scores. In conclusion, deep medullary vein engorgement was common in our patients with neurosarcoidosis. Although its pathophysiology remains uncertain, it could be related to venous or perivenous abnormalities and may represent a useful secondary finding of cerebrovascular disease.


Increase in K+ and alpha-AIB active transport in CHO cells after low [K+] treatment.
We have studied the effects of prolonged incubation in low [K+] medium (approximately 0.3 mM) on both K+ and amino acid transport in Chinese hamster ovary (CHO) cells. When incubated in low [K+] medium, CHO cells redressed partially the loss of intracellular K+ after 12 h. After 24 h of incubation, both the activity of Na+-K+-ATPase in crude homogenates, and the transport capacity (Vmax) for ouabain-sensitive (i.e., active) K+ influx approximately doubled. The magnitude of the ouabain-insensitive (i.e., passive) K+ influx decreased by 50%. Thus the regulatory response involves an apparent increase in Na+-K+ pump and a decrease in K+ leak. The transport capacity for the nonmetabolized amino acid, alpha-aminoisobutyric acid (alpha-AIB), also increased after 24 h in low [K+] medium. The Vmax for the Na+-dependent (i.e., active) alpha-AIB influx increased by about 150%, and the magnitude of the Na+-independent influx increased by 20-40%. These changes in alpha-AIB transport result in a twofold greater capacity to accumulate this amino acid. Thus the regulation of K+ and alpha-AIB transport systems appears to be linked and possible mechanisms of this linkage are discussed.


[Combined middle and inner ear abnormality: report of a case].
Congenital anomalies of the middle ear associated to anomalies of the inner ear are rarely described. Our case displays a malformation due to an association of congenital absence of the round window and aplasia of the semi-circular canals, causing conductive hearing loss. First diagnosis was a congenital atresia isolated of the round window, related to a previous surgical exploration. We tried a novel technique designed to restore the function of the round window. Labyrinthine anomalies prevented a good outcome. This kind of malformative association could be due to the complexity of early genetic control of ear development. Attentive analysis of imaging should be performed before middle ear surgery to determine the presence of inner ear anomalies which are quite frequent and which would limit its usefulness.


An informational diversity framework, illustrated with sexually deceptive orchids in early stages of speciation.
Reconstructing evolutionary history for emerging species complexes is notoriously difficult, with newly isolated taxa often morphologically cryptic and the signature of reproductive isolation often restricted to a few genes. Evidence from multiple loci and genomes is highly desirable, but multiple inputs require 'common currency' translation. Here we deploy a Shannon information framework, converting into diversity analogue, which provides a common currency analysis for maternally inherited haploid and bi-parentally inherited diploid nuclear markers, and then extend that analysis to construction of minimum-spanning networks for both genomes. The new approach is illustrated with a quartet of cryptic congeners from the sexually deceptive Australian orchid genus Chiloglottis, still in the early stages of speciation. Divergence is more rapid for haploid plastids than for nuclear markers, consistent with the effective population size differential (N(ep) < (N(en)), but divergence patterns are broadly correlated for the two genomes. There are nevertheless intriguing discrepancies between the emerging plastid and nuclear signals of early phylogenetic radiation of these taxa, and neither pattern is entirely consistent with the available information on the sexual cues used by the orchids to lure the pollinators enforcing reproductive isolation. We describe possible extensions of this methodology to multiple ploidy levels and other types of markers, which should increase the range of application to any taxonomic assemblage in the very early stages of reproductive isolation and speciation.


Features of endoscopic procedure site reaction associated with a recently approved submucosal lifting agent.
Endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), are frequently aided by injection of submucosal lifting solutions that create a plane for dissection and protect deeper mural layers. ORISE™ gel is a recently approved synthetic lifting solution that produces a localized inflammatory reaction associated with retained gel at the injection site. We describe a series of six cases of ORISE™-associated inflammatory lesions in patients who underwent endoscopic resections. Deposits comprised pale fibrillary or hyalinized eosinophilic material, depending on their age. All cases were associated with an inflammatory reaction composed of foreign-body giant cells and scattered eosinophils. ORISE™ gel extended laterally and deeply beyond residual tumors in all cases. Histochemically, the material proved to be negative for Congo Red, and mucicarmine, faint blue with Alcian blue, but positive for PAS and PAS-D. It stained blue with trichrome. Such deposits were absent in cases, wherein other widely-available lifting solutions were used. We compared ORISE™ deposits to histologically similar extracellular deposits, namely amyloid and pulse granulomata. Unlike ORISE™ material, amyloid deposits appear as waxy, more densely eosinophilic material, and stain positive with Congo Red. Amyloid demonstrated prominent intramucosal and perivascular distributions, features not seen in this series of ORISE™ deposits. Hyalinized pulse granulomata showed strong overlap with ORISE™ deposits, since they also comprise eosinophilic material associated with giant cell reaction. On the other hand, they form ribbons of glassy material in circumscribed lobules, unlike the ill-defined ORISE™ deposits. In summary, we describe the pathologic findings at injection sites in patients who underwent endoscopic procedures aided by the recently approved lifting agent, ORISE™. Pathologists should be aware of its appearance and associated reaction to avoid confusion with other common extracellular deposits seen in the gastrointestinal tract.


Cytoplasmic localization of the transforming protein of Fujinami sarcoma virus: salt-sensitive association with subcellular components.
Fujinami sarcoma virus (FSV) encodes a transforming protein of 130,000 daltons (P130) which is associated with a tyrosine-specific protein kinase activity. To elucidate mechanisms involved in cell transformation by FSV, we have studied the intracellular location of P130 in rat cells nonproductively infected with FSV. Immunofluorescent staining of several FSV-transformed rat cell lines with a tumor regressor antiserum specific against the fps sequences of P130 showed that the major staining was localized in the cytoplasm. Staining was also seen in cell ruffles and in some cases at areas of cell contact. The cytoplasmic location of P130 staining in cells infected with temperature-sensitive mutants of FSV was unchanged when they were grown at permissive or nonpermissive temperature. Cell fractionation of FSV-transformed cells under various conditions showed that the ionic strength used during cell fractionation had a striking effect on the distribution of P130. At 10 mM NaCl, 70% of P130 sedimented in the large granule fraction, whereas at 500 mM NaCl 70 to 90% of P130 was recovered in the cytosol fraction. Furthermore, a combination of ionic and nonionic detergents that effectively solubilized subcellular membranes was insufficient to solubilize P130 unless the salt concentration was raised. We conclude that the majority of P130 and its associated protein kinase activity are localized in the cytoplasm and that P130 is not an integral membrane protein.


The Otto Aufranc Award: Demineralized bone matrix around porous implants promotes rapid gap healing and bone ingrowth.
Noncemented revision arthroplasty is often complicated by the presence of bone implant gaps that reduce initial stability and biologic fixation. Demineralized bone matrix has osteoinductive properties and therefore the potential to enhance gap healing and porous implant fixation. We determined at what times and to what extent demineralized bone matrix promotes gap healing and bone ingrowth around a porous implant. We inserted porous titanium implants into the proximal metaphyses of canine femora and humeri, with an initial 3-mm gap between host cancellous bone and implants. We left the gaps empty (control; n = 12) or filled them with either demineralized bone matrix (n = 6) or devitalized demineralized bone matrix (negative control; n = 6) and left them in situ for 4 or 12 weeks. We quantified volume healing of the gap with new bone using three-dimensional micro-CT scanning and quantified apposition and ingrowth using backscattered scanning electron microscopy. The density of bone inside gaps filled with demineralized bone matrix reached 64% and 93% of surrounding bone density by 4 and 12 weeks, respectively. Compared with empty controls and negative controls at 4 and 12 weeks, gap healing using demineralized bone matrix was two to three times greater and bone ingrowth and apposition were up to 15 times greater. Demineralized bone matrix promotes rapid bone ingrowth and gap healing around porous implants. Demineralized bone matrix has potential for enhancing implant fixation in revision arthroplasty.


Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier.
Nuclear DNA is the canonical target for biological damage induced by Auger electrons (AE) in the context of targeted radionuclide therapy (TRT) of cancer, but other subcellular components might also be relevant for this purpose, such as the energized mitochondria of tumor cells. Having this in mind, we have synthesized novel DOTA-based chelators carrying a prostate-specific membrane antigen (PSMA) inhibitor and a triphenyl phosphonium (TPP) group that were used to obtain dual-targeted 111In-radioconjugates ([111In]In-TPP-DOTAGA-PSMA and [111In]In-TPP-DOTAGA-G3-PSMA), aiming to promote a selective uptake of an AE-emitter radiometal (111In) by PSMA+ prostate cancer (PCa) cells and an enhanced accumulation in the mitochondria. These dual-targeted 111In-radiocomplexes are highly stable under physiological conditions and in cell culture media. The complexes showed relatively similar binding affinities toward the PSMA compared to the reference tracer [111In]In-PSMA-617, in line with their high cellular uptake and internalization in PSMA+ PCa cells. The complexes compromised cell survival in a dose-dependent manner and in the case of [111In]In-TPP-DOTAGA-G3-PSMA to a higher extent than observed for the single-targeted congener [111In]In-PSMA-617. μSPECT imaging studies in PSMA+ PCa xenografts showed that the TPP pharmacophore did not interfere with the excellent in vivo tumor uptake of the "golden standard" [111In]In-PSMA-617, although it led to a higher kidney retention. Such kidney retention does not necessarily compromise their usefulness as radiotherapeutics due to the short tissue range of the Auger/conversion electrons emitted by 111In. Overall, our results provide valuable insights into the potential use of mitochondrial targeting by PSMA-based radiocomplexes for efficient use of AE-emitting radionuclides in TRT, giving impetus to extend the studies to other AE-emitting trivalent radiometals (e.g., 161Tb or 165Er) and to further optimize the designed dual-targeting constructs.


Non-atherosclerotic causes of acute coronary syndromes.
Atherosclerosis and plaque disruption have a central pathological role in the majority of patients who present with an acute coronary syndrome (ACS), but non-atherosclerotic processes are also important contributors to a substantial number of ACS events and require different diagnostic and therapeutic strategies. In the absence of obstructive coronary artery disease, intravascular imaging techniques might be needed to delineate the underlying aetiology, together with a high index of suspicion for other important causes of ACS. In this Review, we discuss five non-atherosclerotic causes of ACS, including spontaneous coronary artery dissection, coronary artery embolism, vasospasm, myocardial bridging and stress-induced cardiomyopathy (Takotsubo syndrome). Important diagnostic findings, management strategies and prognostic data for these non-atherosclerotic mechanisms of ACS are reviewed.


Insight of druggable cannabinoids against estrogen receptor β in breast cancer.
Breast cancer (BC) is the second most prevalent cancer worldwide. Estrogen receptor beta (ERβ) is an essential protein of breast cells to suppress estrogen-induced uncontrolled proliferation. Thus, small molecules that can modulate and enhance ERβ expression would be an effective agent to suppress BC development. Studies showed that cannabinoid (CB), specifically delta-9-tetrahydrocannabinol (Del9THC), can increase the expression of ERβ and inhibits BC cell proliferation. In this study, less psychoactive and structurally similar analogs of Del9THC were chosen as drug candidates and ERβ was targeted as a therapeutic receptor. Delta-8-tetrahydrocannabinol (Del8THC) and delta-4-isotetrahydrocannabinol (Del4isoTHC) were the drug candidates selected on the basis of literature reports, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features. Molecular docking simulations were carried out to determine ligand receptor interactions and binding affinity based on free binding energy. To get a better drug, the structural modification was done on Del8THC and generated a new CB analog called Cannabinoid A. Finally, molecular interaction analysis revealed that two CBs and one of their analog interact with the active site residues of ERβ. Therefore, this study revealed a new way to discover novel drug(s) for BC patients.Communicated by Ramaswamy H. Sarma.


On the use of local weather types classification to improve climate understanding: An application on the urban climate of Toulouse.
This paper proposes a method based on a local weather type classification approach to facilitate analysis and communication of climate information in local climate studies. Presented herein is an application to urban climatology in Toulouse, France, but the method can be used in other applied fields of climatology as well. To describe the climatic context of this urbanized area, the local weather types that explain the plurality of weather situations Toulouse faces are presented in depth. In order to show the potential for use of this approach, this information is applied to the study of changes in local weather types in terms of frequency and intensity within a series of future climate projections, a classic urban canopy and a series of atmospheric boundary layer analyses, and as a support for communication aimed to initiate urban climate awareness in urban planning practices. The proposed classification method has been coded in an R script and is provided as a supporting information file. The paper concludes that a systematic pre-study using this kind of climatic analysis is a good practice for performing climatic contextualization in local scale applied studies, both for scientific analysis and communication.


Evidence-based practices in addiction treatment: review and recommendations for public policy.
The movement in recent years towards evidence-based practice (EBP) in health care systems and policy has permeated the substance abuse treatment system, leading to a growing number of federal and statewide initiatives to mandate EBP implementation. Nevertheless, due to a lack of consensus in the addiction field regarding procedures or criteria to identify EBPs, the optimal processes for disseminating empirically based interventions into real-world clinical settings have not been identified. Although working lists of interventions considered to be evidence-based have been developed by a number of constituencies advocating EBP dissemination in addiction treatment settings, the use of EBP lists to form policy-driven mandates has been controversial. This article examines the concept of EBP, critically reviews criteria used to evaluate the evidence basis of interventions, and highlights the manner in which such criteria have been applied in the addictions field. Controversies regarding EBP implementation policies and practices in addiction treatment are described, and suggestions are made to shift the focus of dissemination efforts from manualized psychosocial interventions to specific skill sets that are broadly applicable and easily learned by clinicians. Organizational and workforce barriers to EBP implementation are delineated, with corresponding recommendations to facilitate successful dissemination of evidence-based skills.


[Long-term results after lunate replacement by the vascularised os pisiform for treatment of Kienböck's disease III b].
Saffar's procedure is used only rarely today. In order to assess the value of this operation in the treatment of advanced Kienböck's disease, after a mean follow-up period of 19 years we could review 7 of 12 patients who had had their lunate replaced by the vascularised pisiform. At the time of follow-up all patients were fully employed without restrictions, and no patient had had to change his job. The mean DASH score was 5.9. The average pain level by VAS was 0.9 and four patients were totally free of pain. Grip strength of the affected arm was reduced to 77% of the opposite side, the active range of motion (extension/flection) was 97 degrees, which was 72% of that of the not affected side. All patients reported high satisfaction with the results of the operation. Although the clinical results were very good, we found substantial radiographical alterations: In 5 patients we found an advanced intercarpal osteoarthritis. Four patients presented a spontaneous synostosis between the pisiform and the triquetrum. The average CHR (carpal height ratio) was 0.43. The presented long-term results after lunate replacement by the vascularised pisiform indicate a high patient satisfaction and very good functional results in spite of significant radiological changes.


Magnetic poly(vinylpyridine)-coated carbon nanotubes: an efficient supramolecular tool for wastewater purification.
Herein, we report the first example of a supramolecular carbon nanotube (CNT)-based magnetic depolluting agent for divalent metal ion (M(2+)) removal from aqueous solutions. In particular, magnetic multi-walled carbon nanotubes (m-MWCNTs) coated with poly(vinylpyridine) (PVPy) self-aggregate in aqueous solutions that contain divalent metal ions (such as Zn(2+), Cu(2+) and Pb(2+)) to form tight insoluble bundles in which the M(2+) ions remain trapped through pyridyl-M(2+)-pyridyl interactions. Magnetic filtration ultimately affords the efficient separation of the depolluted solution from the precipitated M(2+)-CNT agglomerates. Upon acid treatment, the supramolecular threads could be disassembled to afford the free CNT-polymer hybrid, thus allowing recycling of the depolluting agent. All materials and complexation/decomplexation steps were thoroughly characterised by using thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), transmission and scanning electron microscopy (TEM and SEM, respectively). The quantification of the M(2+) residual concentrations in water was evaluated by using inductively coupled plasma optical emission spectroscopy (ICP-OES), which showed that, depending on the metal cation, this material can remove up to 99% of the contaminant.


A randomized, placebo-controlled study of once-daily atomoxetine in the school setting in children with ADHD.
Five studies have demonstrated the effectiveness of atomoxetine compared with placebo in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) based on parent reports. The primary objective of this clinical trial was to assess the efficacy of once-daily atomoxetine compared with placebo using teacher reports. One hundred fifty-three patients aged 8-12 years were randomly assigned to receive once-daily atomoxetine or placebo in a 2:1 ratio for 7 weeks. ADHD symptoms at school were primarily assessed by baseline-to-endpoint change on the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Teacher Version: Investigator administered and scored (ADHDRS-IV-Teacher:Inv) as rated by investigators using teacher reports. ADHDRS-IV-Teacher:Inv total scores were significantly lower for children treated with atomoxetine compared with those treated with placebo (p = .001). Similar results were observed for the inattentive (p = .016) and hyperactive/impulsive (p < .001) ADHDRS-IV-Teacher:Inv subscales, the clinician-rated Clinical Global Impressions severity scale (p = .001), the Conners Global Index-Teacher scale (p = .008), and the Conners Parent Rating Scale-Revised: Short Form ADHD Index T-Score (p < .001). Discontinuations due to adverse events were low in both groups (atomoxetine 5.9%, placebo 0%, p = .096). This study extends previous results based on parent reports showing that once-daily administration of atomoxetine is safe and effective in improving ADHD symptoms in children and demonstrates that outcomes at school are similar when symptoms are reported by teachers.