Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor.
Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to treat HPIV3 or RSV infections. We recently reported a peptide (VIQKI), derived from the C-terminal heptad repeat (HRC) domain of the HPIV3 fusion (F) glycoprotein that inhibits infection by both HPIV3 and RSV. The dual inhibitory activity of VIQKI is due to its unique ability to bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F, thereby preventing the native HRN-HRC interactions required for viral entry. Here we describe the structure-guided design of dual inhibitors of HPIV3 and RSV fusion with improved efficacy. We show that VIQKI derivatives possessing one (I456F) or two (I454F/I456F) phenylalanine substitutions near the N-terminus exhibit more stable assemblies with the RSV-HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Cocrystal structures of the new Phe-substituted inhibitors coassembled with HPIV3 or RSV-HRN domains reveal that the I456F substitution makes intimate hydrophobic contact with the core trimers of both HPIV3 and RSV F.


Reported physical and sexual abuse in childhood and adult HIV risk behaviour in three African countries: findings from Project Accept (HPTN-043).
Childhood sexual and physical abuse have been linked to adolescent and adult risky sexual behaviors, including early sexual debut, an increased number of sexual partners, unprotected sex, alcohol and drug use during sex and sexual violence. This paper explores these relationships among both men and women who report histories of childhood abuse from representative samples of communities in three countries in southern and eastern Africa (South Africa, Zimbabwe and Tanzania). Data were collected as part of a 3-year randomized community trial to rapidly increase knowledge of HIV status and to promote community responses through mobilisation, mobile testing, provision of same-day HIV test results and post-test support for HIV. The results indicate that reported childhood sexual and physical abuse is high in all three settings, also among men, and shows strong relationships with a range of sexual risk behaviors, including age at first sex (OR -0.6 (CI: -0.9, -0.4, p < 0.003)-among men, OR -0.7 (CI: -0.9, -0.5, p < 0.001)-among women), alcohol (OR 1.43 (CI: 1.22, 1.68, p < 0.001)-men, OR 1.83 (CI: 1.50, 2.24, p < 0.001)-women) and drug use (OR 1.65 (CI: 1.38, 1.97, p < 0.001)-men, OR 3.14 (CI: 1.95, 5.05, p < 0.001)-women) and two forms of partner violence-recent forced sex (OR 2.22 (CI: 1.66, 2.95, p < 0.001)-men, OR 2.76 (CI: 2.09, 3.64, p < 0.001)-women) and ever being hurt by a partner (OR 3.88 (CI: 2.84, 5.29, p < 0.001)-men, OR 3.06 (CI: 2.48, 3.76, p < 0.001)-women). Individuals abused in childhood comprise between 6 and 29 % of young adult men and women living in these African settings and constitute a population at high risk of HIV infection.


DNA barcoding of the medically important freshwater snail Physa acuta reveals multiple invasion events into Africa.
The medically important freshwater snail Physa acuta is highly invasive and has been reported in several freshwater environments across Africa. To identify species and provide initial insights into the origins of P. acuta into African freshwater environments standard molecular barcoding analyses, using the mitochondrial cytochrome c oxidase subunit I gene (COI), was performed on P. acuta isolates from Angola, Burundi and South Africa. Phylogenetic analyses of isolates from Africa could not be distinguished from P. acuta populations from other countries. Comparisons of COI sequences between isolates of P. acuta showed there to be no geographically specific clusters and the African isolates were distributed across four distinct unrelated clades suggesting several independent invasion events. Haplotype analyses indicated that there were a high number of haplotypes with low variation between them, which led to significant differences in AMOVA analyses between countries. This was further evidence of multiple invasion events suggesting multiple novel haplotypes being continually and independently introduced to each country. This approach not only provides initial insight into the invasion of Africa by P. acuta but a molecular method to monitor and manage the use of an agent of biological control.


Clinical reliability of radial forearm free-flap procedure in reconstructive head and neck surgery.
The purpose of the study was to evaluate the indications, reliability, and complications of the radial forearm fasciocutaneous flap (RFFF) procedure in reconstructive head and neck surgery. The records of 81 patients who were treated with an RFFF between 1998 and 2009 were systematically reviewed. Data of recipient localization, previous T status, and postoperative complications were analyzed. From the 50 male and 31 female patients, 4 patients (3 men and 1 woman) experienced flap failure during the first 36 hours: in 1 patient because of arterial and in 3 patients because of venous complications. None of the 4 patients had preoperative radiotherapy. A dehiscence was observed in 2 patients without a need for further surgery. With a success rate of more than 95%, the RFFF is a reliable flap and a workhorse, particularly in defects where thinness is needed to substitute for the oral mucosa, such as on the floor of the mouth or the tongue.


High phobic anxiety is related to lower leukocyte telomere length in women.
Chronic psychological distress has been linked to shorter telomeres, an indication of accelerated aging. Yet, little is known about relations of anxiety to telomeres. We examined whether a typically chronic form of anxiety--phobic anxiety--is related to telomere length. Relative telomere lengths (RTLs) in peripheral blood leukocytes were measured by quantitative real-time polymerase chain reaction among 5,243 women (aged 42-69 years) who: were participants in the Nurses' Health Study; were controls in prior case-control studies of telomeres and disease, or randomly selected healthy participants in a cognitive function sub-study; had completed the Crown-Crisp phobic index proximal to blood collection. Adjusted least-squares mean RTLs (z-scores) were calculated across phobic categories. Higher phobic anxiety was generally associated with lower RTLs (age-adjusted p-trend = 0.09); this association was similar after adjustment for confounders--paternal age-at-birth, smoking, body mass index (BMI) and physical activity (p-trend = 0.15). Notably, a threshold was identified. Among women with Crown-Crisp<6 points, the multivariable-adjusted least-squares mean RTL z-score = 0.02 standard units; however, among the most phobic women (Crown-Crisp ≥ 6), the multivariable-adjusted least-squares mean RTL z-score = -0.09 standard units (mean difference = -0.10 standard units; p = 0.02). The magnitude of this difference was comparable to that for women 6 years apart in age. Finally, effect modification by BMI, smoking and paternal age was observed: associations were stronger among highly phobic women with BMI ≥ 25 kg/m(2), without smoking history, or born to fathers aged ≥ 40 years. In this large, cross-sectional study high phobic anxiety was associated with shorter telomeres. These results point toward prospective investigations relating anxiety to telomere length change.


Effects of the neutral endopeptidase inhibitor, SCH 42495, on the cardiovascular remodelling secondary to chronic hypoxia in rats.
1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495. 2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage. 3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n = 8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level. 4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control hypoxic groups at day 10. 5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.


Factors that impact the timely treatment of obstetric fistulas in Malawi: The perspective of health care providers.
In sub-Saharan African countries, women face a high risk of obstetric fistulas. In Malawi, the prevalence rate is 1 per 1000 women. Studies suggest that several obstacles exist that prevent obstetric fistula patients from getting timely treatment for their condition. The aim of this article was to find out the factors that delay the timely treatment of obstetric fistula patients at Malawian hospitals. The study was conducted at the Queen Elizabeth Central Hospital, a referral hospital, situated in Blantyre, Malawi, and the findings have been generalised to all the hospitals in Malawi. An exploratory case study, employing key interview questions, was used to provide insights into why there are delays in providing treatment and care for fistula patients. Purposive sampling technique was used to identify study respondents. Key informant interviews were conducted with 16 health care personnel at a hospital in Malawi. The presence of numerous cases of complicated obstetric fistula cases overwhelms the health care system in Malawi. In addition, the severe shortage of staff, lack of obstetric fistula surgery training, low staff morale, inadequate infrastructure or equipment and water scarcity in the city of Blantyre contribute towards delayed treatment of fistulas at the hospitals. The presence of numerous cases of obstetric fistulas is overwhelming health services, and hence there is a need for devising and implementing health policies that will motivate Malawian health personnel to undertake obstetric fistula surgery and care.


Expression and methylation pattern of p16 in neuroblastoma tumorigenesis.
Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.


Spermiogenesis and spermatozoon of the tapeworm Ligula intestinalis (Diphyllobothriidea): phylogenetic implications.
Using transmission electron microscopy, spermiogenesis and the spermatozoon ultrastructural organization are described in Ligula intestinalis (Linnaeus, 1758) (Diphyllobothriidea), a parasite of the great crested grebe Podiceps cristatus (Linnaeus, 1758). Spermiogenesis starts with the differentiation zone of 2 striated rootlets, 2 centrioles giving rise to 2 flagella, and an intercentriolar body. The latter is composed of 5 electron-dense layers separating 4 electron-lucent layers. In the early stages of spermiogenesis, an electron-dense material is present in the apical region of the differentiation zone. Later, the flagella undergo a rotation and fuse with the cytoplasmic extension in a proximo-distal process. The spermatozoon contains 2 axonemes with a 9 + "1" trepaxonematan pattern, the nucleus, the cortical microtubules, and an electron-dense zone. The spermatozoon anterior extremity in L. intestinalis is characterized by the absence of crested bodies and a ring of electron-dense cortical microtubules. Some characters of spermiogenesis and spermatozoon in L. intestinalis confirm the recent splitting of "Pseudophyllidea" into 2 new orders, i.e., Bothriocephalidea and Diphyllobothriidea. The process of spermiogenesis is similar in both orders for the "type I" of spermiogenesis and the presence of electron-dense material. However, the intercentriolar body is clearly more developed in the Diphyllobothriidea than in the Bothriocephalidea. Moreover, these 2 orders seem to differ in the presence or absence of a ring of electron-dense cortical microtubules in the anterior extremity of the spermatozoon.


Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.
We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.


Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro.
Cystinosis is a rare disease caused by homozygous mutations of the CTNS gene, encoding a cystine efflux channel in the lysosomal membrane. In Ctns knockout mice, the pathologic intralysosomal accumulation of cystine that drives progressive organ damage can be reversed by infusion of wildtype bone marrow-derived stem cells, but the mechanism involved is unclear since the exogeneous stem cells are rarely integrated into renal tubules. Here we show that human mesenchymal stem cells, from amniotic fluid or bone marrow, reduce pathologic cystine accumulation in co-cultured CTNS mutant fibroblasts or proximal tubular cells from cystinosis patients. This paracrine effect is associated with release into the culture medium of stem cell microvesicles (100-400 nm diameter) containing wildtype cystinosin protein and CTNS mRNA. Isolated stem cell microvesicles reduce target cell cystine accumulation in a dose-dependent, Annexin V-sensitive manner. Microvesicles from stem cells expressing CTNS(Red) transfer tagged CTNS protein to the lysosome/endosome compartment of cystinotic fibroblasts. Our observations suggest that exogenous stem cells may reprogram the biology of mutant tissues by direct microvesicle transfer of membrane-associated wildtype molecules.


Antibiotics for acute pyelonephritis in children.
Urinary tract infection (UTI) is one of the most common bacterial infections in infants. The most severe form of UTI is acute pyelonephritis, which results in significant acute morbidity and may cause permanent kidney damage. There remains uncertainty regarding the optimum antibiotic regimen, route of administration and duration of treatment. This is an update of a review that was first published in 2003 and updated in 2005 and 2007. To evaluate the benefits and harms of antibiotics used to treat children with acute pyelonephritis. The aspects of therapy considered were 1) different antibiotics, 2) different dosing regimens of the same antibiotic, 3) different duration of treatment, and 4) different routes of administration. We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, reference lists of articles and conference proceedings without language restriction to 10 April 2014. Randomised and quasi-randomised controlled trials comparing different antibiotic agents, routes, frequencies or durations of therapy in children aged 0 to 18 years with proven UTI and acute pyelonephritis were selected. Four authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). This updated review included 27 studies (4452 children). This update included evidence from three new studies, and following re-evaluation, a previously excluded study was included because it now met our inclusion criteria.Risk of bias was assessed as low for sequence generation (12 studies), allocation concealment (six studies), blinding of outcome assessors (17 studies), incomplete outcome reporting (19 studies) and selective outcome reporting (13 studies). No study was blinded for participants or investigators. The 27 included studies evaluated 12 different comparisons. No significant differences were found in duration of fever (2 studies, 808 children: MD 2.05 hours, 95% CI -0.84 to 4.94), persistent UTI at 72 hours after commencing therapy (2 studies, 542 children: RR 1.10, 95% CI 0.07 to 17.41) or persistent kidney damage at six to 12 months (4 studies, 943 children: RR 0.82, 95% CI 0.59 to 1.12) between oral antibiotic therapy (10 to 14 days) and intravenous (IV) therapy (3 days) followed by oral therapy (10 days). Similarly, no significant differences in persistent bacteriuria at the end of treatment (4 studies, 305 children: RR 0.78, 95% CI 0.24 to 2.55) or persistent kidney damage (4 studies, 726 children: RR 1.01, 95% CI 0.80 to 1.29) were found between IV therapy (three to four days) followed by oral therapy and IV therapy (seven to 14 days). No significant differences in efficacy were found between daily and thrice daily administration of aminoglycosides (1 study, 179 children, persistent clinical symptoms at three days: RR 1.98, 95% CI 0.37 to 10.53). Adverse events were mild and uncommon and rarely resulted in discontinuation of treatment. This updated review increases the body of evidence that oral antibiotics alone are as effective as a short course (three to four days) of IV antibiotics followed by oral therapy for a total treatment duration of 10 to 14 days for the treatment of acute pyelonephritis in children. When IV antibiotics are given, a short course (two to four days) of IV therapy followed by oral therapy is as effective as a longer course (seven to 10 days) of IV therapy. If IV therapy with aminoglycosides is chosen, single daily dosing is safe and effective. Insufficient data are available to extrapolate these findings to children aged less than one month of age or to children with dilating vesicoureteric reflux (grades III-V). Further studies are required to determine the optimal total duration of antibiotic therapy required for acute pyelonephritis.


Nonexercise movement in elderly compared with young people.
The association between free-living daily activity and aging is unclear because nonexercise movement and its energetic equivalent, nonexercise activity thermogenesis, have not been exhaustively studied in the elderly. We wanted to address the hypothesis that free-living nonexercise movement is lower in older individuals compared with younger controls matched for lean body mass. Ten lean, healthy, sedentary elderly and 10 young subjects matched for lean body mass underwent measurements of nonexercise movement and body posture over 10 days using sensitive, validated technology. In addition, energy expenditure was assessed using doubly labeled water and indirect calorimetry. Total nonexercise movement (acceleration arbitrary units), standing time, and standing acceleration were significantly lower in the elderly subjects; this was specifically because the elderly walked less distance per day despite having a similar number of walking bouts per day compared with the young individuals. The energetic cost of basal metabolic rate, thermic effect of food, total daily energy expenditure, and nonexercise activity thermogenesis were not different between the elderly and young groups. Thus, the energetic cost of walking in the elderly may be greater than in the young. Lean, healthy elderly individuals may have a biological drive to be less active than the young.


[PAHO focuses on the problem of violence against women].
In Latin American and the Caribbean, a woman who is abused by her partner tends to deny the fact that she is the object of violence out of embarrassment, fear of revenge on the part of the assailant, or tacit consent on the part of the family and society at large. If she finally appeals to the justice or health care system, no one alleviates her circumstances, since both sectors operate independently and less efficiently than if intersectoral coordination existed. In June 1994 PAHO initiated a project in 16 countries involving the creation within the community of branches of the justice and health care systems, police, churches, non-government organizations, and community groups. These meet on a regular basis with the aim of launching a coordinated response to domestic violence. At the national level, the project fosters policies and legal norms that strengthen the institutional capacity to respond to the problem. Links with the media are also being promoted in order to combat social beliefs and attitudes that lead to women being abused in their own homes.


Identification of enolases and aldolases as important fish allergens in cod, salmon and tuna: component resolved diagnosis using parvalbumin and the new allergens.
The majority of fish-allergic patients are sensitized to parvalbumin, known to be the cause of important IgE cross-reactivity among fish species. Little is known about the importance of fish allergens other than parvalbumin. The aim of this study was to characterize hitherto undefined fish allergens in three commonly consumed fish species, cod, salmon and tuna, and to evaluate their importance for in vitro IgE-diagnosis in addition to parvalbumin and fish gelatin. Sixty-two patients were diagnosed by clinical history, skin prick tests and specific IgE to fish extracts. Two new fish allergens from cod, salmon and tuna were identified by microsequencing. These proteins were characterized by immunoblot, ELISA and mediator release assay. Purified parvalbumin, enolase, aldolase and fish gelatin were used for quantification of specific IgE in ELISA. Parvalbumin and two other allergens of 50 and 40 kDa were detected in IgE-immunoblots of cod, salmon and tuna extracts by most patient sera. The 50 and 40 kDa proteins were identified as beta-enolase and fructose-bisphosphate aldolase A respectively. Both purified enzymes showed allergenic activity in the mediator release assay. Indeed, 72.6% of the patients were sensitized to parvalbumin, 20% of these had specific IgE to salmon parvalbumin only. IgE to enolases were found in 62.9% (0.5-95.0 kUA /L), to aldolases in 50.0% (0.4-26.0 kUA /L) and to fish gelatin in 19.3% (0.4-20.0 kUA /L) of the patients. Inter-species cross-reactivity, even though limited, was found for enolases and aldolases by IgE-inhibition ELISA. Fish enolase and aldolase have been identified as important new fish allergens. In fish allergy diagnosis, IgE to enolase and aldolase are especially relevant when IgE to parvalbumin are absent.


Ballistic characterization of the Remington Premier Copper Solid sabot shotgun slug.
We evaluated the impact and penetration characteristics of the Remington Copper Solid sabot shotgun slug with standardized ballistic tests and used this information to predict tissue wounding patterns. This unique ammunition, first distributed in 1993, is composed of a solid copper, hollow-point slug with longitudinal slots cut into the nose. The slug is fitted into a hard plastic sabot with 8 finger-like projections and loaded into a shotgun shell with two plastic wads separating it from the underlying gunpowder charge. The ammunition was fired through a 12-gage shotgun using a rifled barrel, a smooth-bore barrel with rifled choke, and a smooth-bore barrel with a smooth modified choke into targets consisting of poster board and 10% ballistic gelatin at a variety of distances. The copper slug and plastic sabot created single 8-fingered asterisk-shaped defects in the poster board when fired at distances of less than 7 to 9 ft (approximately 2 to 3 m). All three barrel types performed similarly. At greater distances, the sabot impacted the targets separately from the slugs and created variably shaped defects that reflected base-first, nose-first, and side-first impacts. Increasing muzzle-to-target distances generally increased the impact distances between the slug and sabot. There was no predictable relationship between the sabot and slug impact points for any of the three barrel types. With each barrel tested, the wads created separate defects from the slug at distances greater than 5 ft (1.5 m). The distances between the slug and the wad impact points increased with increasing muzzle-to-target distances up to 40 ft (12 m), after which the wads generally no longer struck the targets. The slug created atypical defects at distances between 7 and 150 ft (approximately 2 to 45 m), probably due to yawing or tumbling. When the slug impacted the gelatin block in a nose-first orientation, the slotted nose portion tended to fragment and radially deposit pieces in the gelatin that were visible on radiographs. When the slug struck the gelatin target in a side-first orientation, it passed through the gelatin intact. The slug, sabot, and wads of this unique projectile separate and create independent impact points in a stereotypical manner independent of barrel type. This pattern of separation allows estimates to be made of ranges of fire. Wounds created in human tissues by this ammunition would likely have similar asterisk-shaped configurations, and nose fragments may be deposited in tissues and seen radiographically. Rectangular wounds created by the tumbling or yawing slug might be mistaken for intermediate target wounds.


Specific inhibition of herpes simplex virus DNA polymerase by helical peptides corresponding to the subunit interface.
The herpes simplex virus DNA polymerase consists of two subunits--a catalytic subunit and an accessory subunit, UL42, that increases processivity. Mutations affecting the extreme C terminus of the catalytic subunit specifically disrupt subunit interactions and ablate virus replication, suggesting that new antiviral drugs could be rationally designed to interfere with polymerase heterodimerization. To aid design, we performed circular dichroism (CD) spectroscopy and analytical ultracentrifugation studies, which revealed that a 36-residue peptide corresponding to the C terminus of the catalytic subunit folds into a monomeric structure with partial alpha-helical character. CD studies of shorter peptides were consistent with a model where two separate regions of alpha-helix interact to form a hairpin-like structure. The 36-residue peptide and a shorter peptide corresponding to the C-terminal 18 residues blocked UL42-dependent long-chain DNA synthesis at concentrations that had no effect on synthesis by the catalytic subunit alone or by calf thymus DNA polymerase delta and its processivity factor. These peptides, therefore, represent a class of specific inhibitors of herpes simplex virus DNA polymerase that act by blocking accessory-subunit-dependent synthesis. These peptides or their structures may form the basis for the synthesis of clinically effective drugs.


Missed Acute Appendicitis on Multidetector Computed Tomography and Magnetic Resonance Imaging: Legal Ramifications, Challenges, and Avoidance Strategies.
The failure to diagnose acute appendicitis (AA) is the third most common medical malpractice allegation related to gastrointestinal disease. There is a paucity of detailed data on this topic; however, publications by Whang et al and by Berlin and Berlin, which analyzed all types of malpractice suits against radiologists, have shown that the incidence of litigation has increased over time in the United States. This is likely true for cases of AA as well. The misinterpretation of cross-sectional imaging in patients with suspected appendicitis may be caused by suboptimal technique, errors of omission, i.e, missing key findings, failure to review a portion of the examination, and satisfaction of search error. This article summarizes the published legal, clinical, and imaging literature regarding litigation in cases of missed AA, and reviews optimized multidetector computed tomography and magnetic resonance imaging protocols for the diagnosis of AA, with examples shown of challenging cases.


The effect of human placenta extract in a wound healing model.
Human placenta had been used on wound healing such as burns, chronic ulcers, and skin defects. Recently, human placenta has been widely used in the form of human placental extracts (HPE) by clinical field. However, it is unclear what the effect of HPE is on wound healing. We studied the effect and mechanism of HPE on wound healing.In this study, 10 mice (imprinting control region mice, 5 week old males, 30 g) were divided into an experimental group and a control group. An 8-mm diameter single full-thickness skin defect was made on the back by skin punch biopsy. At least 2.0 x 10 mL/30 g HPE was injected into the boundaries of the wound. Wound size measurements were taken by digital image every 3 days over 2 weeks. Hematoxylin and eosin (H and E), transforming growth factor beta (TGF-beta), vascular endothelial growth factor (VEGF), and CD31+ immunohistochemical stains were performed on the 6th and 14th day.The experimental group showed acceleration in the decrease of wound size compared with the control group from the third day to the ninth day. TGF-beta on the 6th day showed a statistically significant increase in the experimental group. VEGF on the 14th day showed a statistically significant increase in the experimental group. CD31+ was increased in the experimental group as wound healing progressed, but this increase was not statistically significant. The total number of vessels increased in the experimental group, but this was not statistically significant.We conclude that administering HPE directly to a wound margin promoted wound healing. This mechanism appears to be related to an increase in TGF-beta in the early phase of wound healing and VEGF in the late phase.


The Use of Tissue Glue for Circumcision in Children: Systematic Review and Meta-analysis.
To evaluate the efficacy of tissue glue in pediatric circumcision. A systematic review and meta-analysis of the English literature (1997-2017) was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement on children who underwent circumcision with tissue glue. Meta-analysis was conducted using RevMan 5.3, Comprehensive Meta-Analysis 2, and MedCalc 18. P values <.05 were considered significant. The search returned 15 studies for a total of 4567 circumcisions, of which 3045 (66%) were performed with tissue glue. The systematic review indicated that overall complication rates were 4.3% (tissue glue) and 5.9% (sutures). The use of tissue glue was associated with reduced postoperative pain, better cosmetic results, and reduced cost. Meta-analysis showed that there was no difference between the incidence of total postoperative complications (relative risk [RR] 0.86 [95% confidence interval {CI}: 0.62-1.19], P = .36) and wound infection and dehiscence between the 2 groups (RR 0.95 [95% CI: 0.59-1.56], P = .85). Postoperative bleeding and hematoma formation were reduced with the use of tissue glue (RR 0.55 [95% CI: 0.32-0.95], P = .03). Tissue glue also significantly shorten the operative time (mean difference -0.22 [95% CI: -0.39 to -0.05], P = .01). The incidence of postoperative bleeding and hematoma formation in pediatric circumcision is reduced with the use of tissue glue. Tissue glue has reduced operative time; furthermore, it might be associated with reduced postoperative pain, less overall cost, and superior cosmetic results.


Semi-quantitative assessment of the intersystem crossing rate: an extension of the El-Sayed rule to the emissive transition metal complexes.
The main goal of this study is to provide systematic elucidation of the parameters that influence S → T intersystem crossing (ISC). Particular attention is paid to: (i) the computation of Sn→ Tm spin-orbit coupling strength based on a non-adiabatic approach, (ii) crucial factors that facilitate ISC, such as the atomic number, ligand structure, and particularly the types of electronic transition, (iii) formulating a discussion on the standpoints of the fundamental photophysical theory. Combining the theoretical and empirical approaches, we then make semi-quantitative assessment of the ISC rate for certain representative transition metal (TM) complexes, the results of which allow us to develop a set of empirical rules that harness ISC for organometallics analogous to El-Sayed's rule for the classic organic compounds. We therefore present a critical and timely theoretical approach with the results matching quantitatively the experimental data, which serves as a prototype to access the photophysics of TM complexes in a facile and precise manner beneficial to researchers in the field of optoelectronics.


Actions of norepinephrine in the rat hippocampus.
Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.


Factors associated with delay in presentation among younger patients with oral cancer.
Despite the reported increase in the incidence of oral squamous cell carcinoma (OSCC) in under 45-year-olds, little is known regarding the pattern and reasons for delay in presentation in this younger age group. The aim of this study was to investigate factors predictive of patient (primary) delay in a sample of 53 newly diagnosed patients under the age of 45 years. Multiple logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for primary delay (> or = 21 days between patient first noticing signs or symptoms and seeking professional advice). Self-reported delay ranged from less than 1 week to 104 weeks, with a median of 5 weeks. A total of 33 patients (62%) reported a delay of at least 21 days. Three variables: lack of further education, perceptions of being under stress in the period prior to diagnosis, and lower amounts of tobacco smoked per day were included in the final model and together explained 43% of the variance in patient delay (R2 = 0.432). Although OSCC is relatively rare in this age group, the rise in incidence and the change in profile of risk factors may increase the odds of patient delay. This has important implications for increasing sign and symptom awareness among the public and primary health care professionals such as general medical practitioners and general dentists.


The chemopreventive effects of Protandim: modulation of p53 mitochondrial translocation and apoptosis during skin carcinogenesis.
Protandim, a well defined dietary combination of 5 well-established medicinal plants, is known to induce endogenous antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Our previous studies have shown through the induction of various antioxidant enzymes, products of oxidative damage can be decreased. In addition, we have shown that tumor multiplicity and incidence can be decreased through the dietary administration of Protandim in the two-stage skin carcinogenesis mouse model. It has been demonstrated that cell proliferation is accommodated by cell death during DMBA/TPA treatment in the two-stage skin carcinogenesis model. Therefore, we investigated the effects of the Protandim diet on apoptosis; and proposed a novel mechanism of chemoprevention utilized by the Protandim dietary combination. Interestingly, Protandim suppressed DMBA/TPA induced cutaneous apoptosis. Recently, more attention has been focused on transcription-independent mechanisms of the tumor suppressor, p53, that mediate apoptosis. It is known that cytoplasmic p53 rapidly translocates to the mitochondria in response to pro-apoptotic stress. Our results showed that Protandim suppressed the mitochondrial translocation of p53 and mitochondrial outer membrane proteins such as Bax. We examined the levels of p53 and MnSOD expression/activity in murine skin JB6 promotion sensitive (P+) and promotion-resistant (P-) epidermal cells. Interestingly, p53 was induced only in P+ cells, not P- cells; whereas MnSOD is highly expressed in P- cells when compared to P+ cells. In addition, wild-type p53 was transfected into JB6 P- cells. We found that the introduction of wild-type p53 promoted transformation in JB6 P- cells. Our results suggest that suppression of p53 and induction of MnSOD may play an important role in the tumor suppressive activity of Protandim.


Relationship of vitamin D status to adult lung function and COPD.
There is considerable interest in the possible role of vitamin D in respiratory disease, but only one population-based study has reported associations with lung function. The cross-sectional relationships of total dietary vitamin D intake, serum 25 hydroxy vitamin D (25(OH)D) concentrations and three vitamin D receptor (VDR) polymorphisms (Apa1, Fok1 and Cdx2) with lung function and spirometrically-defined chronic obstructive pulmonary disease (COPD) were investigated in men and women aged 59-73 years in the Hertfordshire Cohort Study, UK. After controlling for confounders, total vitamin D intake was positively associated with forced expiratory volume in 1 s (FEV(1); difference in FEV(1) between top and bottom quintiles of intake 0.079 l (95% CI 0.02 to 0.14), p trend=0.007, n=2942), ratio of FEV(1) to forced vital capacity (FEV(1)/FVC; p trend=0.008) and negatively associated with COPD (OR comparing top and bottom quintiles 0.57 (95% CI 0.38 to 0.87), p trend=0.02). In contrast, serum 25(OH)D concentrations were not related to FEV(1) (p trend=0.89, n=1197) but were positively associated with COPD (p trend=0.046). VDR genotypes were unrelated to lung function and did not modify the effects of dietary intake or 25(OH)D concentrations on lung function. The results of this study did not confirm a positive association between blood 25(OH)D concentrations and adult lung function. The apparent relationships with dietary vitamin D are likely to be explained by other highly correlated nutrients in the diet.


Determination of Markers of Successful Implementation of Mental Health Apps for Young People: Systematic Review.
Smartphone apps have the potential to address some of the current issues facing service provision for young people's mental health by improving the scalability of evidence-based mental health interventions. However, very few apps have been successfully implemented, and consensus on implementation measurement is lacking. This review aims to determine the proportion of evidence-based mental health and well-being apps that have been successfully adopted and sustained in real-world settings. A secondary aim is to establish if key implementation determinants such as coproduction, acceptability, feasibility, appropriateness, and engagement contribute toward successful implementation and longevity. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, an electronic search of 5 databases in 2021 yielded 18,660 results. After full-text screening, 34 articles met the full eligibility criteria, providing data on 29 smartphone apps studied with individuals aged 15 to 25 years. Of 34 studies, only 10 (29%) studies were identified that were evaluating the effectiveness of 8 existing, commercially available mental health apps, and the remaining 24 (71%) studies reported the development and evaluation of 21 newly developed apps, of which 43% (9/21) were available, commercially or otherwise (eg, in mental health services), at the time of enquiry. Most studies addressed some implementation components including adoption, acceptability, appropriateness, feasibility, and engagement. Factors including high cost, funding constraints, and lengthy research processes impeded implementation. Without addressing common implementation drivers, there is considerable redundancy in the translation of mobile mental health research findings into practice. Studies should embed implementation strategies from the outset of the planned research, build collaborations with partners already working in the field (academic and commercial) to capitalize on existing interventions and platforms, and modify and evaluate them for local contexts or target problems and populations. PROSPERO CRD42021224365; https://tinyurl.com/4umpn85f.


The effects of antenatal corticosteroids and surfactant replacement on neonatal respiratory distress syndrome.
The goal of this study was to determine the effects of antenatal corticosteroids and surfactant replacement on the severity and frequency of Respiratory Distress Syndrome (RDS) in a cohort of premature infants born in Sarajevo, Bosnia and Herzegovina, from 2005 to 2007. The cohort consisted of 172 premature neonates with estimated gestational age between 26 and 34 weeks. Babies with IUGR, babies of diabetic mothers and babies with major congenital defects were excluded. Out of 172 neonates, 80 were treated antenatally with corticosteroids (single course of dexamethasone) and 92/172 were not. There was no statistical difference (p>0,5) in average gestational age (31,2 vs. 31,0 GW) and male/female ratio between investigated groups; there were significantly more male patients (p<0,05) in both groups. Frequency of RDS was significantly lower in the corticosteroid group (24/80) in relation to the control group (54/92) (p<0,001). Severe RDS was significantly (p<0,01) more frequent in the control group 34/53 (62,96%) then in the corticosteroid group 6/24 (25,0%). Bovine surfactant (Survanta) was given as a rescue therapy to 78 babies with clinical and radiological signs of RDS who required FiO2>0,40 and mechanical ventilation. Early surfactant administration within six hours after birth appeared to be effective at reducing mortality then later surfactant administration (p<0,005). In the group of babies requiring FiO2> or =0,6 at the time of surfactant replacement, the mortality rate was significantly higher (p<0,05). In conclusion, we confirm the efficacy of antenatal corticosteroid treatment and early surfactant treatment in a cohort of premature infants born in Sarajevo.


Multimodal in vivo imaging exposes the voyage of nanoparticles in tumor microcirculation.
Tumors present numerous biobarriers to the successful delivery of nanoparticles. Decreased blood flow and high interstitial pressure in tumors dictate the degree of resistance to extravasation of nanoparticles. To understand how a nanoparticle can overcome these biobarriers, we developed a multimodal in vivo imaging methodology, which enabled the noninvasive measurement of microvascular parameters and deposition of nanoparticles at the microscopic scale. To monitor the spatiotemporal progression of tumor vasculature and its vascular permeability to nanoparticles at the microcapillary level, we developed a quantitative in vivo imaging method using an iodinated liposomal contrast agent and a micro-CT. Following perfusion CT for quantitative assessment of blood flow, small animal fluorescence molecular tomography was used to image the in vivo fate of cocktails containing liposomes of different sizes labeled with different NIR fluorophores. The animal studies showed that the deposition of liposomes depended on local blood flow. Considering tumor regions of different blood flow, the deposition of liposomes followed a size-dependent pattern. In general, the larger liposomes effectively extravasated in fast flow regions, while smaller liposomes performed better in slow flow regions. We also evaluated whether the tumor retention of nanoparticles is dictated by targeting them to a receptor overexpressed by the cancer cells. Targeting of 100 nm liposomes showed no benefits at any flow rate. However, active targeting of 30 nm liposomes substantially increased their deposition in slow flow tumor regions (∼12-fold increase), which suggested that targeting prevented the washout of the smaller nanoparticles from the tumor interstitium back to blood circulation.


Elevated levels of the polo kinase Cdc5 override the Mec1/ATR checkpoint in budding yeast by acting at different steps of the signaling pathway.
Checkpoints are surveillance mechanisms that constitute a barrier to oncogenesis by preserving genome integrity. Loss of checkpoint function is an early event in tumorigenesis. Polo kinases (Plks) are fundamental regulators of cell cycle progression in all eukaryotes and are frequently overexpressed in tumors. Through their polo box domain, Plks target multiple substrates previously phosphorylated by CDKs and MAPKs. In response to DNA damage, Plks are temporally inhibited in order to maintain the checkpoint-dependent cell cycle block while their activity is required to silence the checkpoint response and resume cell cycle progression. Here, we report that, in budding yeast, overproduction of the Cdc5 polo kinase overrides the checkpoint signaling induced by double strand DNA breaks (DSBs), preventing the phosphorylation of several Mec1/ATR targets, including Ddc2/ATRIP, the checkpoint mediator Rad9, and the transducer kinase Rad53/CHK2. We also show that high levels of Cdc5 slow down DSB processing in a Rad9-dependent manner, but do not prevent the binding of checkpoint factors to a single DSB. Finally, we provide evidence that Sae2, the functional ortholog of human CtIP, which regulates DSB processing and inhibits checkpoint signaling, is regulated by Cdc5. We propose that Cdc5 interferes with the checkpoint response to DSBs acting at multiple levels in the signal transduction pathway and at an early step required to resect DSB ends.


Natural treatment of chronic rhinosinusitis.
Chronic rhinosinusitis (CRS) is one of the most common long-term illnesses in the United States, affecting approximately 14 percent of the population. CRS is a challenging condition to treat, partly due to its multifaceted, poorly understood pathophysiology. Treatment goals include maintaining open drainage and decreasing inflammation while improving tissue integrity and limiting causative factors. This review covers the etiology, pathology, and diagnosis of CRS, as well as mainstream and alternative treatments. Discussion of alternative therapeutics includes nutrients and botanicals (ascorbic acid, bromelain, N-acetylcysteine, quercetin, undecylenic acid, and Urtica dioica and other herbal medicines) and procedures (nasal irrigation and naso-sympatico treatments). The influences of diet and air quality on CRS are also discussed.


Molecular pathways of endothelial cell activation for (targeted) pharmacological intervention of chronic inflammatory diseases.
In chronic inflammatory conditions, endothelial cells actively recruit immune cells from the circulation into the underlying tissue and participate in angiogenesis to support the continuous demand for oxygen and nutrients. They do so in response to activation by cytokines and growth factors such as tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), and fibroblast growth factors (FGFs). Receptor triggering initiates intracellular signal transduction leading to activation of nuclear factor kappaB (NFkappaB), mitogen activated protein kinase (MAPK) activity, and nitric oxide and reactive oxygen species production, among others. As a result, adhesion molecules, cytokines and chemokines, and a variety of other genes are being expressed that mediate and control the inflammatory process. In recent years, different classes of drugs have been developed that interfere with selected enzymes involved in the intracellular signalling cascades. In endothelial cell cultures, they exert potent inhibitory effects on the expression of genes, while several studies also report on in vivo effectiveness to confine the inflammatory responses. To prevent undesired toxicity and to improve drug behaviour and efficacy, drug carrier systems have been developed that selectively deliver the therapeutics into the activated endothelial cells. The above subjects are recapitulated to give an overview on the status of development of endothelial cell directed therapeutic strategies to pharmacologically interfere with chronic inflammatory diseases.


Benign paroxysmal positional vertigo.
Benign paroxysmal positional vertigo (BPPV) has received renewed clinical interest. At the Johns Hopkins Otological Vestibular Laboratory, 781 patients were tested on more than one occasion between September 1976 and November 1992. Of these patients, 187 (24%) were found to have positional nystagmus consistent with a diagnosis of BPPV. A retrospective analysis of these patients' records, including vestibular test and eye movement reports, audiograms, questionnaires, and hospital charts was performed. After this review, the nystagmus, initially diagnosed as due to BPPV, was believed to be a manifestation of another disease process in 36 cases. Of the remaining 151 cases, 52 (34%) presented with no significant preceding disorder and have been termed primary BPPV. In the remaining 99 patients we found coexisting or associated disorders which included Meniere's disease, head trauma, prior ear surgery, vestibular neuronitis, migraine, and others. Forty-five of these 151 patients (31%) had an associated diagnosis of Meniere's disease. To our knowledge a significant association between Meniere's disease and BPPV has not been reported. A review of the literature with discussion of BPPV and the associated disorders is offered.


Mucocele of the surgically isolated esophagus.
A large esophageal mucocele causing chest pain developed in a 26-year-old woman who had undergone esophageal bypass surgery and gastric interposition because of involvement by scleroderma. Computed tomographic (CT) scans showed the mucocele as an elongated mediastinal mass which spontaneously reduced in size during conservative management. The clinical and radiological features of this unusual postsurgical complication are herein reviewed.


Coverage and Consumption of Micronutrient Powders, Fortified Staples, and Iodized Salt Among Children Aged 6 to 23 Months in Selected Neighborhoods of Nairobi County, Kenya.
Intake of micronutrient-rich foods among children aged 6 to 23 months in Nairobi is low. This study aimed to assess existing coverage and utilization of micronutrient powders (MNPs), fortified staples, and iodized salt among children aged 6 to 23 months prior to implementation of an MNP program. A cross-sectional survey among caregivers of children aged 6 to 23 months (n = 618) was implemented in 7 neighborhoods within Nairobi County, representing the implementation area of the new MNP program. Results for MNP coverage and utilization showed 28.5% of all caregivers were aware of MNP, 18.5% had ever received MNP for their child, and 10.8% had fed MNP to their child in the previous 7 days. Effective coverage (ie, the child had been given the MNP at least 3 times in the previous 7 days) was 5.8%. Effective coverage of infants and young children with poor feeding practices was significantly lower as compared to those with non-poor feeding practices (coverage ratio, 0.34; confidence interval, 0.12-0.70). Most households purchased iodized salt (96.9%), fortified oil (61.0%), and fortified maize flour (93.9%). An estimated 23.9% of vitamin A requirements of children (6-23 months) were provided from fortified oil and 50.7% of iron from fortified maize flour. Most households consumed processed milk (81%). Coverage of MNPs in the surveyed neighborhoods was low. Coverage of fortified salt, oil, and maize flour was high and provided significant amount of micronutrients to children. Processed milk has potential as a vehicle for food fortification.


Long-term effects of short-term perturbation in a subalpine grassland.
Theoretical advances and short-term experimental studies have furthered our understanding of how ecosystems respond to perturbation. However, there are few well-replicated experimental studies that allow an assessment of long-term responses. Results from a controlled, large-scale field experiment in a subalpine grassland near Interlaken, Switzerland, show that 2-4 years of liming (Ca: 40 g x m(-2) x yr(-1)) still significantly affected the composition of the vegetation and the soil microbial community nearly 70 years after the treatments were imposed, whereas NPK fertilization (8 g x m(-2) x yr(-1)) only marginally affected vegetation composition. The exchangeable content of Ca ions and soil pH were higher in limed plots but were unaffected in fertilized plots. Plant species and PLFAs (phospholipid fatty acids) indicating low pH values were found in higher abundance in the unlimed plots, suggesting that the long-lasting effects of liming on the above- and belowground communities were mediated through changes in soil pH. The results of this long-term study indicate that the resilience of mountain ecosystems may be particularly low in response to perturbations that substantially alter soil pH or other key determinants of belowground processes.


[New variants of diagnostic procedures and therapeutic methods in insect venom allergy].
Hymenoptera venom allergy (HVA) is a typical IgE-dependent allergy. Its diagnosis includes confirmation of the presence of specific IgE antibodies to venom allergens (vsIgE), and its treatment is based on developing of immunotolerance (venom immunotherapy, VIT). In most cases of sting anaphylaxis, vsIgE can be found, in some, however, the antibodies are undetectable, in spite of systemic reaction to venom, which may be due to low specificity of diagnostic methods. Diagnostic methods might be improved by the use of recombinant allergens which, being "uncontaminated" by other venom constituents, allow for a precise setup of "individual allergogram." A diagnostic novelty is the tryptase serum level assay that is capable of confirming ex-post anaphylaxis and coincidence of mastocytosis. The diagnostic procedures applied in venom allergy make possible only to prove the existence of allergy while it is impossible to estimate, on their basis, the risk of development and intensification of future reactions. New diagnostic concept that could supplement the imperfect diagnostic armamentarium is still lacking. Clinical practice has proven that VIT is a very effective method of protection of patients with IgE-dependent wasp-sting anaphylaxis, but both the effectiveness and safety of VIT in patients allergic to bee venom are not optimal. The future of VIT is the use of modified, recombinant allergens or their peptide fragments, but clinical data on their effectiveness are unavailable as yet. The safety of VIT can be increased by means of introducing premedication with antihistamines.


A comparison of 3-T magnetic resonance imaging and computed tomography arthrography to identify structural cartilage defects of the fetlock joint in the horse.
Articular cartilage defects are prevalent in metacarpo/metatarsophalangeal (MCP/MTP) joints of horses. The aim of this study was to determine and compare the sensitivity and specificity of 3-Tesla magnetic resonance imaging (3-T MRI) and computed tomography arthrography (CTA) to identify structural cartilage defects in the equine MCP/MTP joint. Forty distal cadaver limbs were imaged by CTA (after injection of contrast medium) and by 3-T MRI using specific sequences, namely, dual-echo in the steady-state (DESS), and sampling perfection with application-optimised contrast using different flip-angle evolutions (SPACE). Gross anatomy was used as the gold standard to evaluate sensitivity and specificity of both imaging techniques. CTA sensitivity and specificity were 0.82 and 0.96, respectively, and were significantly higher than those of MRI (0.41 and 0.93, respectively) in detecting overall cartilage defects (no defect vs. defect). The intra and inter-rater agreements were 0.96 and 0.92, respectively, and 0.82 and 0.88, respectively, for CT and MRI. The positive predictive value for MRI was low (0.57). CTA was considered a valuable tool for assessing cartilage defects in the MCP/MTP joint due to its short acquisition time, its specificity and sensitivity, and it was also more accurate than MRI. However, MRI permits assessment of soft tissues and subchondral bone and is a useful technique for joint evaluation, although clinicians should be aware of the limitations of this diagnostic technique, including reduced accuracy.


Peptide-Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite-Mediated Nitration.
Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half-life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio-inspired peptide-based NO sensor is developed, which detects NO-derived oxidants, predominately peroxynitrite-mediated nitration of tyrosine residues. It is demonstrated that these peptide-based NO sensors can detect peroxynitrite-mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide-conjugated fluorescent particle immunoassay, peroxynitrite-mediated nitration activity with a detection limit of ≈100 × 10-9 m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell-based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.


The cost-effectiveness of hypertension management in low-income and middle-income countries: a review.
Hypertension in low-income and middle-income countries (LMICs) is largely undiagnosed and uncontrolled, representing an untapped opportunity for public health improvement. Implementation of hypertension control strategies in low-resource settings depends in large part on cost considerations. However, evidence on the cost-effectiveness of hypertension interventions in LMICs is varied across geographical, clinical and evaluation contexts. We conducted a comprehensive search for published economic evaluations of hypertension treatment programmes in LMICs. The search identified 71 articles assessing a wide range of hypertension intervention designs and cost components, of which 42 studies across 15 countries reported estimates of cost-effectiveness. Although comparability of results was limited due to heterogeneity in the interventions assessed, populations studied, costs and study quality score, most interventions that reported cost per averted disability-adjusted life-year (DALY) were cost-effective, with costs per averted DALY not exceeding national income thresholds. Programme elements that may reduce cost-effectiveness included screening for hypertension at younger ages, addressing prehypertension, or treating patients at lower cardiovascular disease risk. Cost-effectiveness analysis could provide the evidence base to guide the initiation and development of hypertension programmes.


Extranodal natural-killer/t-cell lymphoma, nasal type.
The World Health Organization (WHO) classification recognizes 2 main categories of natural killer (NK) cell-derived neoplasms, namely, extranodal NK/T-cell lymphoma, nasal type, and aggressive NK-cell leukaemia. Extranodal nasal NK/T-cell lymphoma is more frequent in the Far East and Latin America. Histopathological and immunophenotypical hallmarks include angiocentricity, angiodestruction, expression of cytoplasmic CD3 epsilon (ε), CD56, and cytotoxic molecules and evidence of Epstein-Barr virus (EBV) infection. Early stage disease, in particular for localized lesion in the nasal region, is treated with chemotherapy and involved-field radiotherapy. On the other hand, multiagent chemotherapy is the mainstay of treatment for advanced or disseminated disease. L-asparaginase-containing regimens have shown promise in treating this condition. The role of autologous hematopoietic stem cell transplantation is yet to be clearly defined. Allogeneic hematopoietic stem cell transplantation, with the putative graft-versus-lymphoma effect, offers a potentially curative option in patients with advanced disease.


Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by event-related functional magnetic resonance imaging.
Although extensive evidence exists for the reinforcing properties of drugs of abuse such as cocaine, relatively less research has addressed the functional neuroanatomical correlates of the cognitive sequelae of these drugs. We present a functional magnetic resonance imaging study of a GO-NOGO task in which successful performance required prepotent behaviors to be inhibited. Significant cingulate, pre-supplementary motor and insula hypoactivity was observed for both successful NOGOs and errors of commission in chronic cocaine users relative to cocaine-naive controls. This attenuated response, in the presence of comparable activation levels in other task-related cortical areas, suggests cortical and psychological specificity in the locus of drug abuse-related cognitive dysfunction. The results suggest that addiction may be accompanied by a disruption of brain structures critical for the higher-order, cognitive control of behavior.


Phenylalanine hydroxylase misfolding and pharmacological chaperones.
Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH(4)) cofactor as query structure for shape-focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH(4). Furthermore, PAH shares a number of ligands, such as BH(4), amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH-chaperoning compounds represent novel possibilities in the treatment of PKU.


Parvimico materdei gen. et sp. nov.: A new platyrrhine from the Early Miocene of the Amazon Basin, Peru.
Three field seasons of exploration along the Río Alto Madre de Dios in Peruvian Amazonia have yielded a fauna of micromammals from a new locality AMD-45, at ∼12.8°S. So far we have identified the new primate described here as well as small caviomorph rodents, cenolestoid marsupials, interatheriid notoungulates, xenarthrans, fish, lizards and invertebrates. The site is in the Bala Formation as exposed where the river transects a syncline. U-Pb dates on detrital zircons constrain the locality's age at between 17.1 ± 0.7 Ma and 18.9 ± 0.7 Ma, making the fauna age-equivalent to that from the Pinturas Formation and the older parts of the Santa Cruz Formation of Patagonian Argentina (Santacrucian). The primate specimen is an unworn M1 of exceptionally small size (equivalent in size to the extant callitrichine, Callithrix jacchus, among the smallest living platyrrhines and the smallest Eocene-Early Miocene platyrrhine yet recorded). Despite its small size it is unlike extant callitrichines in having a prominent cingulum hypocone. Based on the moderate development of the buccal crests, this animal likely had a diet similar to that of frugivorous callitrichines, and distinctly different from the more similarly-sized gummivores, Cebuella and C. jacchus. The phyletic position of the new taxon is uncertain, especially given the autapomorphic character of the tooth as a whole. Nevertheless, its unusual morphology hints at a wholly original and hitherto unknown Amazonian fauna, and reinforces the impression of the geographic separation of the Amazonian tropics from the more geographically isolated southerly parts of the continent in Early Miocene times.


A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.
SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.


Neurogenomic Profiling Reveals Distinct Gene Expression Profiles Between Brain Parts That Are Consistent in Ophthalmotilapia Cichlids.
The detection of external and internal cues alters gene expression in the brain which in turn may affect neural networks that underly behavioral responses. Previous studies have shown that gene expression profiles differ between major brain regions within individuals and between species with different morphologies, cognitive abilities and/or behaviors. A detailed description of gene expression in all macroanatomical brain regions and in species with similar morphologies and behaviors is however lacking. Here, we dissected the brain of two cichlid species into six macroanatomical regions. Ophthalmotilapia nasuta and O. ventralis have similar morphology and behavior and occasionally hybridize in the wild. We use 3' mRNA sequencing and a stage-wise statistical testing procedure to identify differential gene expression between females that were kept in a social setting with other females. Our results show that gene expression differs substantially between all six brain parts within species: out of 11,577 assessed genes, 8,748 are differentially expressed (DE) in at least one brain part compared to the average expression of the other brain parts. At most 16% of these DE genes have |log2FC| significantly higher than two. Functional differences between brain parts were consistent between species. The majority (61-79%) of genes that are DE in a particular brain part were shared between both species. Only 32 genes show significant differences in fold change across brain parts between species. These genes are mainly linked to transport, transmembrane transport, transcription (and its regulation) and signal transduction. Moreover, statistical equivalence testing reveals that within each comparison, on average 89% of the genes show an equivalent fold change between both species. The pronounced differences in gene expression between brain parts and the conserved patterns between closely related species with similar morphologies and behavior suggest that unraveling the interactions between genes and behavior will benefit from neurogenomic profiling of distinct brain regions.


Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration.
Erythropoietin (Epo) has neuroprotective and neurotrophic effects and improves cognitive function in animal models of neurodegenerative and neuropsychiatric illness. In humans, weekly Epo administration over 3 months improves cognitive function in schizophrenia. The neural underpinnings and time-course of this effect of Epo are currently unknown. It is also unclear whether the cognitive improvement reflects direct neurobiological actions or is secondary to hematological effects. We therefore assessed the actions of single administration of Epo (40,000 IU) vs. saline to healthy volunteers on cognitive and neural measures of executive function using a verbal fluency task and N-back working memory (WM) paradigm during functional magnetic resonance imaging (fMRI) on day 3 and 7 after administration in two separate cohorts of subjects. Epo modulated neuronal response in a fronto-parietal network during WM performance at both time points; on day 3 after administration, activation was increased in left-hemisphere frontal and cingulate cortex and reduced in the right parietal cortex; in contrast, neural response was enhanced in a right-lateralized fronto-parietal network and reduced in left-side regions 1 week post-administration. In addition, Epo-treated volunteers displayed improved verbal fluency performance 1 week post-administration. These effects occurred in the absence of changes in hematological measures suggesting that they reflect direct neurobiological actions of Epo. The findings are consistent with enduring effects of Epo on neurotrophic signaling and induction of neurochemical changes over time in neural networks typically affected in neuropsychiatric illness. The present study supports the notion that Epo may have clinical applications in the treatment of psychiatric disorder characterized by cognitive dysfunction.


Combined rule extraction and feature elimination in supervised classification.
There are a vast number of biology related research problems involving a combination of multiple sources of data to achieve a better understanding of the underlying problems. It is important to select and interpret the most important information from these sources. Thus it will be beneficial to have a good algorithm to simultaneously extract rules and select features for better interpretation of the predictive model. We propose an efficient algorithm, Combined Rule Extraction and Feature Elimination (CRF), based on 1-norm regularized random forests. CRF simultaneously extracts a small number of rules generated by random forests and selects important features. We applied CRF to several drug activity prediction and microarray data sets. CRF is capable of producing performance comparable with state-of-the-art prediction algorithms using a small number of decision rules. Some of the decision rules are biologically significant.


Dehydration elevates osmotic threshold for salt gland secretion in the duck.
Acute salt and water balance measurements were made in two conscious salt water-acclimated Pekin ducks at and above their osmotic threshold for salt gland secretion. Intravneous infusion of 1,000 mosmol/kg H2O NaCl at 0.350 ml/min increased plasma tonicity less than 0.5% and increased secretion from nearly zero to a rate matching the infusion. Continuous secretion at a similar submaximal rate was driven by 5,600 mosmol/kg H2O NaCl infused at 0.070 ml/min. Osmolality of secreted fluid was constant for any secretion rate, so that net water loss occurred when the concentration of infusate exceeded that of secreted fluid. Threshold plasma osmolality increased by 9 mosmol/kg H2O after the loss of 77 g water (3% body wt). Solutes were always secreted at the infusion rate, even when body fluid osmolality increased while body water decreased. We conclude that the salt gland controller is sensitive to more than just extracellular fluid (ECF) tonicity, and we suggest that elevation of the osmotic threshold may occur in response to decreased ECF volume.


Searching for Evidence to Support the Use of Ginger in the Prevention of Chemotherapy-Induced Nausea and Vomiting.
Patients with cancer frequently use dietary supplementation and herbal therapies to control symptoms of disease and adverse effects of cancer therapy. Despite the widespread use of dietary supplementation and herbal therapies in oncology, robust scientific evidence in this area is lacking. Not only do these products need to be tested in large and well-designed observational or randomized studies, but their manufacturing process must be improved to achieve higher levels of standardization in product quality. Ginger is frequently used to counteract chemotherapy-induced nausea and vomiting (CINV), and some suggestions that it might be effective against CINV come from randomized and/or crossover clinical trials. However, several limitations in the methods of these studies limit their power and generalizability. The authors are conducting a randomized, double-blind study with a large sample size and homogeneous inclusion criteria in order to evaluate the efficacy of a well-standardized ginger extract in reducing nausea in patients with cancer. The widespread use of standardized herbal therapies and natural components among patients requires that scientific and rigorous research strategies are applied in this field to guide the physicians and the patients in safer use.


Experimental and computational study of the ring opening of tricyclic oxanorbornenes to polyhydro isoindole phosphonates.
Phosphonylated azaheterocycles are an important class of compounds with high biological potential as conformationally restricted bioisosteres of amino acids. Therefore, it is of interest to synthesize conformationally constrained amino phosphonates. We wanted to investigate possible routes via ring opening of alpha-amino phosphonates with an oxanorbornene skeleton, as these can be synthesized with high stereoselectivity. This was achieved using different Lewis acids, leading to a range of products. The reaction with TiCl(4) and FeCl(3) was modelled at a DFT level of theory to get insight in the pathways towards the corresponding products. To ease the work up, the Fe(iii) catalyst was coated on montmorillonite clay, but this accelerated aromatization after ring opening. Quenching the FeCl(3) catalyzed reaction mixture on celite caused complete aromatization.


Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency.
The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.


Vitamin E: action, metabolism and perspectives.
Natural vitamin E includes four tocopherols and four tocotrienols. RRR-alpha-tocopherol is the most abundant form in nature and has the highest biological activity. Although vitamin E is the main lipid-soluble antioxidant in the body, not all its properties can be assigned to this action. As antioxidant, vitamin E acts in cell membranes where prevents the propagation of free radical reactions, although it has been also shown to have pro-oxidant activity. Non-radical oxidation products are formed by the reaction between alpha-tocopheryl radical and other free radicals, which are conjugated to glucuronic acid and excreted through the bile or urine. Vitamin E is transported in plasma lipoproteins. After its intestinal absorption vitamin E is packaged into chylomicrons, which along the lymphatic pathway are secreted into the systemic circulation. By the action of lipoprotein lipase (LPL), part of the tocopherols transported in chylomicrons are taken up by extrahepatic tissues, and the remnant chylomicrons transport the remaining tocopherols to the liver. Here, by the action of the "alpha-tocopherol transfer protein", a major proportion of alpha-tocopherol is incorporated into nascent very low density lipoproteins (VLDL), whereas the excess of alpha-tocopherol plus the other forms of vitamin E are excreted in bile. Once secreted into the circulation, VLDL are converted into IDL and LDL by the action of LPL, and the excess of surface components, including alpha-tocopherol, are transferred to HDL. Besides the LPL action, the delivery of alpha-tocopherol to tissues takes place by the uptake of lipoproteins by different tissues throughout their corresponding receptors. Although we have already a substantial information on the action, effects and metabolism of vitamin E, there are still several questions open. The most intriguing is its interaction with other antioxidants that may explain how foods containing small amounts of vitamin E provide greater benefits than larger doses of vitamin E alone.


Parental Perspectives of a Wearable Activity Tracker for Children Younger Than 13 Years: Acceptability and Usability Study.
There is increasing availability of, and interest in, wearable activity trackers for children younger than 13 years. However, little is known about how children and parents use these activity trackers or perceive their acceptability. This study primarily aimed to ascertain parental perspectives on the acceptability and usability of wearables designed to monitor children's physical activity levels. Secondary aims were to (1) identify practical considerations for future use in physical activity interventions and promotion initiatives; (2) determine use of different features and functions incorporated into the accompanying app; and (3) identify parents' awareness of their child's current physical activity levels. In total, 36 children (18 boys and 18 girls) aged 7-12 years were asked to wear a wrist-worn activity tracker (KidFit) for 4 consecutive weeks and to use the accompanying app with parental assistance and guidance. Each week, one parent from each family (n=25; 21 mothers and 4 fathers) completed a Web-based survey to record their child's activity tracker use, app interaction, and overall experiences. At the end of the 4-week period, a subsample of 10 parents (all mothers) participated in face-to-face interviews exploring perceptions of the acceptability and usability of wearable activity trackers and accompanying apps. Quantitative and qualitative data were analyzed descriptively and thematically, respectively. Thematic data are presented using pen profiles, which were constructed from verbatim transcripts. Parents reported that they and their children typically found the associated app easy to use for activity tracking, though only step or distance information was generally accessed and some difficulties interpreting the data were reported. Children were frustrated with not being able to access real-time feedback, as the features and functions were only available through the app, which was typically accessed by, or in the presence of, parents. Parents identified that children wanted additional functions including a visual display to track and self-monitor activity, access to the app for goal setting, and the option of undertaking challenges against schools or significant others. Other barriers to the use of wearable activity trackers included discomfort of wearing the monitor because of the design and the inability to wear for water- or contact-based sports. Most parents reported that the wearable activity tracker was easy for their child or children to use and a useful tool for tracking their children's daily activity. However, several barriers were identified, which may impact sustained use over time; both the functionality and wearability of the activity tracker should therefore be considered. Overall, wearable activity trackers for children have the potential to be integrated into targeted physical activity promotion initiatives.


Magnesium/silicon atomic weight percent ratio standards for the tissue identification of talc by scanning electron microscopy and energy dispersive X-ray analysis.
Talc may lodge in human tissues through various routes, and has been associated with the development of ovarian carcinoma in case control epidemiologic studies. Talc is detected in tissues with scanning electron microscopy and energy dispersive X-ray analysis (SEM/EDS), with expected magnesium (Mg) and silicon (Si) peaks. The theoretical atomic weight % Mg/Si ratio for talc is 0.649, and for diagnostic purposes, a range of ± 5% (~0.617 to 0.681) is often used as a standard. Our goal was to establish empirically the quantitative range for talc identification by SEM/EDS using two source materials: a Johnson's Baby PowderTM (cosmetic-grade) consumer sample, and talc from Sigma-Aldrich (particle-grade material intended for scientific use). We examined 401 Mg-Si particles with SEM/EDS across the two samples, using two different SEM microscopes. Overall, we found a mean Mg/Si atomic weight % ratio of 0.645, with minimal differences between study subsets. The standard deviation was 0.025; (± 1σ = 0.620-0.670). The currently used ± 5% diagnostic range (Mg/Si 0.617-0.681) is thus reasonably close to this study's ± 1σ range, and well within a ± 2 σ confidence interval span (Mg/Si 0.595-0.695). The ± 5% range is thus an appropriately conservative standard whose continued use seems justified.


Optimization and stabilization of electrodeposited Cu2ZnSnS4 photocathodes for solar water reduction.
Cu2ZnSnS4 (CZTS) is a promising p-type semiconductor that has not yet been extensively investigated for solar fuel production via water splitting. Here, we optimize and compare two different electrodeposition routes (simultaneous and sequential) for preparing CZTS electrodes. More consistent results are observed with the simultaneous route. In addition, the effect of etching and the presence of a CdS buffer layer on the photocurrent are investigated. Finally, we demonstrate for the first time the stabilization of these electrodes using protecting overlayers deposited by atomic layer deposition (ALD). Our best performing protected electrodes (Mo/CZTS/CdS/AZO/TiO2/Pt) exhibited a photocurrent of over 1 mA cm(-2) under standard one sun illumination conditions and a significant improvement in stability over unprotected electrodes.


A longitudinal study of educational differences in antidepressant use before and after hospital care for depression.
Despite social inequalities in depression various studies report small or even reversed social gradients for antidepressant treatment, suggesting unmet need for treatment among those with low social position. However, few studies assess need for treatment or compare longitudinal antidepressant use patterns between socioeconomic groups. We used a nationally representative register cohort of Finnish adults with hospital care for depression in 1998-2007 (n = 7249). We compared the prevalence of any use and daily use of antidepressants across educational groups in consecutive 3-month periods up to 5 years before admission and 5 years after discharge, adjusting for important confounders. We found no educational differences in any antidepressant use in the 5 years leading to hospital care for depression but a 3-4 percentage-point higher prevalence among those with high education in the 3-month periods immediately preceding and following hospital care for depression. Furthermore, decline in the prevalence of antidepressant use after discharge was more rapid in low education resulting in a significant 4-6 percentage-point higher prevalence among the highly educated lasting until 2.5 years after discharge. Daily use was significantly more common among the highly educated for a year before admission, immediately after discharge and for 2.5 years thereafter, the excess being 3-8 percentage-points. Our results suggest rather equitable access to antidepressant treatment at the time of evident need, i.e. immediately after discharge from hospital care for depression. However, early discontinuation of treatment as well as below guideline use of antidepressants were more common among the low educated.


Neuroprotection by plumbagin involves BDNF-TrkB-PI3K/Akt and ERK1/2/JNK pathways in isoflurane-induced neonatal rats.
This study was designed to assess the effects of plumbagin on isoflurane-induced neurotoxicity. Neonatal Sprague Dawley rat pups were treated with plumbagin (50, 100 or 150 mg/kg body weight, orally) from postnatal day 2. The pups on postnatal day 7 were subjected to isoflurane (0.75%) exposure for 6 h. Neuronal apoptosis in the hippocampal tissues was detected by TUNEL assay and FluroJade B staining following isoflurane exposure. Protein expressions were analysed by immunoblotting. RT-PCR was performed to assess mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB. We observed reduced apoptosis in hippocampal CA1, CA3 and dentate gyrus regions along with severely reduced pro-apoptotic factors (Bad, Bax and cleaved caspase-3) expression and raised levels of Bcl-2, Bcl-xL, survivin, xIAP and cIAPs (cell survival proteins) in plumbagin supplemented rats. Decrease in the levels of JNK, phospho-JNK, c-Jun and phospho-c-Jun with enhanced ERK1/2 levels was observed on plumbagin pretreatment. Down-regulated PI3K/Akt signalling following isoflurane was activated by plumbagin as evidenced by raised PI3K/Akt pathway proteins - mTORc1, Akt, phospho-Akt, GSK-3β, phospho-GSK-3β, PTEN and NF-κBp65 in the hippocampal tissues as detected by Western blotting. The mRNA levels were enhanced on plumbagin supplementation. Plumbagin exerted its neuroprotective effects by effectively suppressing isoflurane-induced neuronal apoptosis via regulating BDNF-TrkB-PI3/Akt and ERK/JNK signalling.


Do all portable cases constructed by caddisfly larvae function in defense?
The portable cases constructed by caddisfly larvae have been assumed to act as a mechanical defense against predatory attacks. However, previous studies have compared the survival of caddisflies with different cases, thereby precluding an analysis of the survival benefits of "weaker" case materials. The level of protection offered by caddisfly cases constructed with rock, stick, or leaf material, as well as a no-case control, was investigated against predatory dragonfly nymphs (Anax junius Drury (Anisoptera: Aeshnidae)). A valid supposition is that the cases made of stronger material are more effective at deterring predators. Yet, observations revealed that there was no difference in survival between the case types. All caddisflies with a case experienced high survival in comparison to caddisflies removed from their case. In addition, larvae with stick-cases experienced fewer attacks and captures by dragonflies. These results showed that the presence of a case, regardless of the material used in its construction, offers survival benefits when faced with predatory dragonfly nymphs.


Théodore Flournoy on synesthetic personification.
In 1893, Théodore Flournoy published a landmark book on synesthesia - Des phénomènes de synopsie [Of Synoptic Phenomena]. The book presented a pioneering chapter on synesthetic personification, including numerous striking case examples, and it is frequently cited by twenty-first-century researchers as providing some of the earliest examples of the phenomenon. Flournoy employed a broad definition of personification - the representation of stimuli as concrete and specific individuals or inanimate objects. This definition encompassed a more extensive set of phenomena than the definition used by researchers today and was illustrated by cases that would fall outside of contemporary subtypes of synesthetic personification. Yet, Flournoy's seminal work remains unavailable in English, and the extent of the phenomenon that he described has not been discussed in the contemporary literature. We provide an unabridged translation of Flournoy's chapter "Des personnifications" ["Of Personifications"].


Renal and extra-renal levels of renin mRNA in experimental hypertension.
1. Using a ribonuclease-protection assay, renin mRNA levels were compared in the kidneys, livers, brains, hearts and adrenal glands of two-kidney, one-clip Goldblatt hypertensive rats with those of age-matched control rats at 4 weeks ('early') and 20 weeks ('chronic') after clipping, and in the kidneys and adrenal glands of rats treated for 3 weeks with deoxycorticosterone and salt (deoxycorticosterone-salt hypertension) with those of control rats. 2. While marked changes were observed in kidney renin mRNA levels in all three experimental groups compared with their respective controls, in most of the extra-renal tissue studied minimal, if any, difference was seen in renin mRNA levels between the hypertensive and control rats. 3. The findings suggest that in these extra-renal tissues renin gene expression is differently regulated from that in the kidney, and particularly that it is not profoundly affected by changes in the level of circulating angiotensin II. 4. An increase in renin mRNA was observed in the adrenal glands of the 'chronic' Goldblatt rats, which may be of relevance to the maintenance of hypertension in this model.


Traditional Sheep Consumption by Navajo People in Cameron, Arizona.
Over 500 abandoned uranium mines are located on the Navajo Reservation. Different pathways of environmental uranium exposure have been studied with respect to the Navajo people including water, soil, and plants; however, uranium exposure from traditional Navajo food, specifically mutton (sheep), has not been reported. This study focuses on mutton consumption in the small community of Cameron, Arizona, located in the southwestern region of the Navajo Nation and initiated after community members expressed concern with the uranium exposure of their sheep. Preliminary investigation into the presence of uranium in sheep raised near Cameron showed elevated uranium levels in the kidneys the sheep tested. The goal of this study is to investigate mutton consumption among the Navajo living in Cameron. Mutton is a traditional food of the Navajo, but consumption practices are not well documented. An important aspect of determining the extent of exposure through food consumption is to assess the frequency of consumption. The results of this study indicate the Cameron participants consume mutton most commonly at family gatherings or celebrations. The survey suggests that less mutton is consumed now compared to the past, and there is concern that contaminated mutton may change traditional ceremonies.


The dicer-like1 homolog fuzzy tassel is required for the regulation of meristem determinacy in the inflorescence and vegetative growth in maize.
Plant architecture is determined by meristems that initiate leaves during vegetative development and flowers during reproductive development. Maize (Zea mays) inflorescences are patterned by a series of branching events, culminating in floral meristems that produce sexual organs. The maize fuzzy tassel (fzt) mutant has striking inflorescence defects with indeterminate meristems, fasciation, and alterations in sex determination. fzt plants have dramatically reduced plant height and shorter, narrower leaves with leaf polarity and phase change defects. We positionally cloned fzt and discovered that it contains a mutation in a dicer-like1 homolog, a key enzyme required for microRNA (miRNA) biogenesis. miRNAs are small noncoding RNAs that reduce target mRNA levels and are key regulators of plant development and physiology. Small RNA sequencing analysis showed that most miRNAs are moderately reduced in fzt plants and a few miRNAs are dramatically reduced. Some aspects of the fzt phenotype can be explained by reduced levels of known miRNAs, including miRNAs that influence meristem determinacy, phase change, and leaf polarity. miRNAs responsible for other aspects of the fzt phenotype are unknown and likely to be those miRNAs most severely reduced in fzt mutants. The fzt mutation provides a tool to link specific miRNAs and targets to discrete phenotypes and developmental roles.