Acceptability and preferences for long-acting antiretroviral formulations among people with HIV infection.
The study evaluates the acceptability and preferences for long-acting antiretroviral therapy (LA-ART) among a diverse cohort of people with HIV infection (PWH). It consists of a self-administered survey and chart review of PWH presenting to an HIV clinic in Houston, Texas, between February and June 2018; 374 participants were included; 61% indicated that they were likely or very likely to use LA-ART formulations. When asked about preference, 41% preferred pills, 40% preferred injections, and 18% preferred an implant. The most common benefit reported was eliminating the need to remember taking daily HIV pills (74%); 43% were worried that LA-ART will not be as effective as pills. Participants with a college degree, men who have sex with men, and ART-experienced were more willing to use LA-ART. Participants who reported poor or fair health, or who screened positive for depression or anxiety were significantly less willing to use LA-ART. The likelihood of using LA-ART did not correlate with self-reported adherence and HIV suppression. Patients with difficulty scheduling and attending clinic visits preferred injections and implant over pills. Most participants indicated a willingness to use new LA ART formulations. However, 41% still prefers pills, and those more interested in LA-ART were not less adherent.


Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease.
Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB). We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain. Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme. Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy.


Occupational therapy rehabilitation for sarcoma patients following limb salvage surgery: a scoping review.
Introduction: Sarcomas are rare cancers of bone and soft tissue, and limb salvage surgery is the standard treatment followed by multidisciplinary rehabilitation. The scoping review aimed to summarize the evidence for occupational therapy intervention for adult sarcoma patients following limb salvage surgery.Methods: A review of the literature using a scoping framework was undertaken starting with a systematic database search, followed by an analysis of the literature. The literature was described using a numerical analysis, and the following headings; (a) rehabilitation, (b) activity limitations and participation restrictions, (c) functional outcomes.Findings: Seventeen articles met the review criteria, papers were diverse in study location, type, population, methods and outcomes used. Following limb salvage surgery patients experience functional deficits, activity limitations and participation restrictions in life roles and loss of previous identity. Prehabilitation can influence functional outcomes. Functional activity was found to plateau at 4-12 months following limb salvage surgery, with some patients identifying a need for further rehabilitation.Conclusion: The review identified limited evidence guiding occupational therapy practice for sarcoma patients following limb salvage surgery. Further research is needed to demonstrate the effectiveness of occupational therapy intervention in the early and late stages of rehabilitation and develop evidence based guidelines.Implications for rehabilitationSarcoma patients experience activity limitations and participation restrictions in activities of daily living, work and leisure following limb salvage surgery.Prehabilitation and early intervention can influence functional outcomes.Functional ability may plateau at 4-12 months following limb salvage surgery.Some groups of patients will benefit from late rehabilitation to maximize their rehabilitation potential.


Aetiology of acute meningoencephalitis in Cambodian children, 2010-2013.
Acute meningoencephalitis (AME) is associated with considerable morbidity and mortality in children in developing countries. Clinical specimens were collected from children presenting with AME at two Cambodian paediatric hospitals to determine the major aetiologies associated with AME in the country. Cerebrospinal fluid (CSF) and blood samples were screened by molecular and cell culture methods for a range of pathogens previously associated with AME in the region. CSF and serum (acute and convalescent) were screened for antibodies to arboviruses such as Japanese encephalitis virus (JEV), dengue virus (DENV), and chikungunya virus (CHIKV). From July 2010 through December 2013, 1160 children (one month to 15 years of age) presenting with AME to two major paediatric hospitals were enroled into the study. Pathogens associated with AME were identified using molecular diagnostics, cell culture and serology. According to a diagnostic algorithm, a confirmed or highly probable aetiologic agent was detected in 35.0% (n=406) of AME cases, with a further 9.2% (total: 44.2%, n=513) aetiologies defined as suspected. JEV (24.4%, n=283) was the most commonly identified pathogen followed by Orientia tsutsugamushi (4.7%, n=55), DENV (4.6%, n=53), enteroviruses (3.5%, n=41), CHIKV (2.0%, n=23) and Streptococcus pneumoniae (1.6%, n=19). The majority of aetiologies identified for paediatric AME in Cambodia were vaccine preventable and/or treatable with appropriate antimicrobials.


Influence of Na+ and Mg2+ ions on RNA structures studied with molecular dynamics simulations.
The structure of ribonucleic acid (RNA) polymers is strongly dependent on the presence of, in particular Mg2+ cations to stabilize structural features. Only in high-resolution X-ray crystallography structures can ions be identified reliably. Here, we perform molecular dynamics simulations of 24 RNA structures with varying ion concentrations. Twelve of the structures were helical and the others complex folded. The aim of the study is to predict ion positions but also to evaluate the impact of different types of ions (Na+ or Mg2+) and the ionic strength on structural stability and variations of RNA. As a general conclusion Mg2+ is found to conserve the experimental structure better than Na+ and, where experimental ion positions are available, they can be reproduced with reasonable accuracy. If a large surplus of ions is present the added electrostatic screening makes prediction of binding-sites less reproducible. Distinct differences in ion-binding between helical and complex folded structures are found. The strength of binding (ΔG‡ for breaking RNA atom-ion interactions) is found to differ between roughly 10 and 26 kJ/mol for the different RNA atoms. Differences in stability between helical and complex folded structures and of the influence of metal ions on either are discussed.


Quantifying the bystander-effect of 2.5G mobile telephones on the speech perception of digital hearing aid users.
To quantify the bystander-effect of 2.5G mobile telephones (2.5G-MTs) on the speech perception of digital hearing-aid (dHA) users. Differences in the susceptibility of behind-the-ear (BTE) compared to in-to-the-ear (ITE) dHAs were also assessed. Prospective-comparative study conducted at a tertiary referral centre (ENT Department) and a HA-fitting laboratory. Key-word recognition scores from open-sentence lists were calculated. Power-analysis determined that a minimum of 60 subjects with SNHL (30 in each group), using either BTE or ITE dHAs, were required for reliable study outcomes. Sixty-four adults were tested with a functioning 2.5G-MT at almost physical contact with their ear; thirty subjects used BTE and 34 ITE dHAs. Aided word recognition score differences between studied groups and within each group, while a 2.5G-MT was activated. Cut-off inclusion criterion regarding baseline aided word recognition score was 75%. Baseline aided word recognition scores for ITE dHAs were better compared to BTE ones (p < 0.01). Following the 2.5G-MT activation, this difference disappeared. No statistically significant difference in word recognition was observed between the examined groups, or within the BTE group, from the bystander-effect of the 2.5G-MT. ITE dHAs proved more susceptible to electromagnetic interference (p < 0.05). The bystander-effect of 2.5G-MTs on the speech perception of dHA users is either minimal, or not significant. The observed compatibility has a positive impact on the lives of millions of people worldwide. The long-standing theory of more interference in BTE compared to ITE HAs is not confirmed by the results of the present study. EBM level of evidence: 2c.


First Report of Branched Broomrape (Orobanche ramosa) on Oilseed Rape (Brassica napus), Wild Mustard (Sinapis arvensis), and Wild Vetch (Vicia spp.) in Northern Greece.
Branched broomrape (Orobanche ramosa L.) is a chlorophyll-lacking, root parasitic plant that infects many crops and wild species (2). Plants are densely hairy with minute, glandular hairs, particularly on flowers and upper stems. Stems are erect, often branched just above the ground, and brown to straw yellow. Leaves are sparse, triangular, dark brown or purple, and arranged alternately mainly near the base of the stem. Flowers are numerous, arranged along an upright spike with a lance-shaped bract beneath the flower (about a third of the length of the flower). Petals are pale blue to purple and united into a slender tube approximately 15 mm long with two lips, the upper divided into two lobes and the lower into three lobes. The flowers have two short and two long stamens. During 2010 and 2011, a severe broomrape infection was found in an oilseed rape (Brassica napus L., cvs. Nelson and W31) crop on light-textured soil in northern Greece (Paralimnio-Serres, 41°01'N, 23°32'E, 40 m above sea level), where oriental tobacco (Nicotiana tabacum L.), a susceptible host of branched broomrape, was grown 20 years ago. The field had been cultivated with oilseed rape for three consecutive seasons in rotation with sunflower (Helianthus annuus L.). The infestation of the oilseed rape crop was confirmed in April by digging in the soil (25 to 30 cm deep) to verify attachment of the broomrape to roots of the crop plants. Density of the broomrape ranged from 20 to 120 stems per m2 and broomrape stems were 15 to 30 cm tall. Yield losses were estimated at 30 to 60%. In 2011, branched broomrape was found parasitizing wild mustard (Sinapis arvensis L.) growing as a weed in the oilseed rape field. Attachment of the broomrape was verified on a lateral root of the wild mustard plant near the soil surface, 0.95 m from the main root of the weed. Additionally, branched broomrape was found in April 2010 and 2011 parasitizing wild vetch (Vicia spp.) growing in field margins at the Cotton and Industrial Plants Institute-National Agricultural Research Foundation (Sindos, 40°41'N, 22°48'E, 17 m above sea level). The parasitized vetch plants were growing on light-textured soil. Attachment of the broomrape to roots of the host plants was verified at a 5-cm soil depth. Stems of the parasite were short (7 to 10 cm). The monthly mean air temperature for February (7.3°C), March (9.6°C), and April (14.1°C) and mean soil temperature at a 10-cm depth for February (7.0°C), March (9.5°C), and April (13.4°C), before verification of the broomrape infestation at Sindos, were much lower than the temperature range reported (18 to 23°C) for branched broomrape infestations (1). To our knowledge, this is the first report of O. ramosa on oilseed rape, wild mustard, and wild vetch in northern Greece. Since branched broomrape could be a significant parasite for oilseed rape, which was introduced to Greece as a commercial crop 5 years ago, measures should be taken to avoid significant yield losses from this parasitic plant. References: (1) I. Faithfull and D. McLaren. Landcare Note LC0272. Department of Sustainability and Environment, State of Victoria, Melbourne, Australia, 2004. (2) C. Parker. Pest Manag. Sci. 65:453, 2009.


Pathogens and glioma: a history of unexpected discoveries ushering in novel therapy.
In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley's toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology.


Efficacy and safety of artemether-lumefantrine as treatment for Plasmodium falciparum uncomplicated malaria in adult patients on efavirenz-based antiretroviral therapy in Zambia: an open label non-randomized interventional trial.
HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether-lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL. A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul's Hospital in northern Zambia, involving 152 patients aged 15-65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population. Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841-1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL. AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx.


Gender and iron genes may modify associations between brain iron and memory in healthy aging.
Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.


Nucleic acid polymerases use a general acid for nucleotidyl transfer.
Nucleic acid polymerases catalyze the formation of DNA or RNA from nucleoside-triphosphate precursors. Amino acid residues in the active site of polymerases are thought to contribute only indirectly to catalysis by serving as ligands for the two divalent cations that are required for activity or substrate binding. Two proton-transfer reactions are necessary for polymerase-catalyzed nucleotidyl transfer: deprotonation of the 3'-hydroxyl nucleophile and protonation of the pyrophosphate leaving group. Using model enzymes representing all four classes of nucleic acid polymerases, we show that the proton donor to pyrophosphate is an active-site amino acid residue. The use of general acid catalysis by polymerases extends the mechanism of nucleotidyl transfer beyond that of the well-established two-metal-ion mechanism. The existence of an active-site residue that regulates polymerase catalysis may permit manipulation of viral polymerase replication speed and/or fidelity for virus attenuation and vaccine development.


JSNP: a database of common gene variations in the Japanese population.
JSNP is a repository of Japanese Single Nucleotide Polymorphism (SNP) data, begun in 2000 and developed through the Prime Minister's Millennium Project. The aim of this undertaking is to identify and collate up to 150 000 SNPs from the Japanese population, located in genes or in adjacent regions that might influence the coding sequence of the genes. The project has been carried out by a collaboration between the Human Genome Center (HGC) in the Institute of Medical Science (IMS) at the University of Tokyo and the Japan Science and Technology Corporation (JST). JSNP serves as both a storage site for the Japanese SNPs obtained from the ongoing project and as a facility for public dissemination to allow researchers access to high quality SNP data. A primary motivation of the project is the construction of a basic data set to identify relationships between polymorphisms and common diseases or the reaction to drugs. As such, emphasis has been placed on the identification of SNPs that lie in candidate regions which may affect phenotype but which would not necessarily directly cause disease. Unrestricted access to JSNP and any associated files is available at http://snp.ims.u-tokyo.ac.jp/.


Drosophila Syncrip modulates the expression of mRNAs encoding key synaptic proteins required for morphology at the neuromuscular junction.
Localized mRNA translation is thought to play a key role in synaptic plasticity, but the identity of the transcripts and the molecular mechanism underlying their function are still poorly understood. Here, we show that Syncrip, a regulator of localized translation in the Drosophila oocyte and a component of mammalian neuronal mRNA granules, is also expressed in the Drosophila larval neuromuscular junction, where it regulates synaptic growth. We use RNA-immunoprecipitation followed by high-throughput sequencing and qRT-PCR to show that Syncrip associates with a number of mRNAs encoding proteins with key synaptic functions, including msp-300, syd-1, neurexin-1, futsch, highwire, discs large, and α-spectrin. The protein levels of MSP-300, Discs large, and a number of others are significantly affected in syncrip null mutants. Furthermore, syncrip mutants show a reduction in MSP-300 protein levels and defects in muscle nuclear distribution characteristic of msp-300 mutants. Our results highlight a number of potential new players in localized translation during synaptic plasticity in the neuromuscular junction. We propose that Syncrip acts as a modulator of synaptic plasticity by regulating the translation of these key mRNAs encoding synaptic scaffolding proteins and other important components involved in synaptic growth and function.


Pumping configuration without focusing lenses for a small-sized diode-pumped Nd:YAG slab laser.
We propose an end-pumping method for a small-sized diode-pumped Nd:YAG laser. The miniature Nd:YAG slab is directly coupled to the pump diode without focusing lenses. With the use of total reflection on the slab surfaces, the pump light is confined to the laser mode volume. With a diode-laser power of 890 mW, a TEM(00) output power of 210 mW is obtained.


Meta-adaptation in the auditory midbrain under cortical influence.
Neural adaptation is central to sensation. Neurons in auditory midbrain, for example, rapidly adapt their firing rates to enhance coding precision of common sound intensities. However, it remains unknown whether this adaptation is fixed, or dynamic and dependent on experience. Here, using guinea pigs as animal models, we report that adaptation accelerates when an environment is re-encountered-in response to a sound environment that repeatedly switches between quiet and loud, midbrain neurons accrue experience to find an efficient code more rapidly. This phenomenon, which we term meta-adaptation, suggests a top-down influence on the midbrain. To test this, we inactivate auditory cortex and find acceleration of adaptation with experience is attenuated, indicating a role for cortex-and its little-understood projections to the midbrain-in modulating meta-adaptation. Given the prevalence of adaptation across organisms and senses, meta-adaptation might be similarly common, with extensive implications for understanding how neurons encode the rapidly changing environments of the real world.


Is quality affordable for community health systems? Costs of integrating quality improvement into close-to-community health programmes in five low-income and middle-income countries.
Countries aspiring to universal health coverage view close-to-community (CTC) providers as a low-cost means of increasing coverage. However, due to lack of coordination and unreliable funding, the quality of large-scale CTC healthcare provision is highly variable and routine data about service quality are not trustworthy. Quality improvement (QI) approaches are a means of addressing these issues, yet neither the costs nor the budget impact of integrating QI approaches into CTC programme costs have been assessed. This paper examines the costs and budget impact of integrating QI into existing CTC health programmes in five countries (Ethiopia, Indonesia, Kenya, Malawi, Mozambique) between 2015 and 2017. The intervention involved: (1) QI team formation; (2) Phased training interspersed with supportive supervision; which resulted in (3) QI teams independently collecting and analysing data to conduct QI interventions. Project costs were collected using an ingredients approach from a health systems perspective. Based on project costs, costs of local adoption of the intervention were modelled under three implementation scenarios. Annualised economic unit costs ranged from $62 in Mozambique to $254 in Ethiopia per CTC provider supervised, driven by the context, type of community health model and the intensity of the intervention. The budget impact of Ministry-led QI for community health is estimated at 0.53% or less of the general government expenditure on health in all countries (and below 0.03% in three of the five countries). CTC provision is a key component of healthcare delivery in many settings, so QI has huge potential impact. The impact is difficult to establish conclusively, but as a first step we have provided evidence to assess affordability of QI for community health. Further research is needed to assess whether QI can achieve the level of benefits that would justify the required investment.


A case of sudden death after Japanese encephalitis vaccination.
Japanese encephalitis (JE) virus is estimated to result in 3500-50,000 clinical cases every year, with mortality rates of up to 20-50% and a high percentage of neurological sequelae in survivors. Vaccination is the single most important measure in preventing this disease. Inactivated Vero cell culture-derived JE vaccines have not been linked to any fatalities, and few serious adverse events after vaccination have been reported. Here, we report a case of sudden death in which a 10-year-old boy experienced cardiopulmonary arrest 5 min after receiving a Japanese encephalitis vaccination. He had been receiving psychotropic drugs for the treatment of pervasive developmental disorders. Postmortem examinations were nonspecific, and no signs of dermatologic or mucosal lesions or an elevation of the serum tryptase level, which are characteristic of anaphylaxis, were observed. A toxicological examination revealed that the blood concentrations of the orally administered psychotropic drugs were within the therapeutic ranges. The patient was considered to have died of an arrhythmia that was not directly associated with the vaccination.


Formation of partially ordered oligomers of amyloidogenic hexapeptide (NFGAIL) in aqueous solution observed in molecular dynamics simulations.
A combined total of more than 600.0 ns molecular dynamics simulations with explicit solvent have been carried on systems containing either four peptides or a single peptide to investigate the early-stage aggregation process of an amyloidogenic hexapeptide, NFGAIL (residues 22-27 of the human islet amyloid polypeptide). Direct observation of the aggregation process was made possible by placing four peptides in a box of water with an effective concentration of 158 mg/ml to enhance the rate of aggregation. Partially ordered oligomers containing multistrand beta-sheets were observed which could be the precursory structures leading to the amyloid-forming embryonic nuclei. Comparative simulations on a single peptide suggested that the combined effect of higher peptide concentration and periodic boundary condition promoted compact monomers and the short-range interpeptide interactions favored the beta-extended conformation. Of particular interest was the persistent fluctuation of the size of the aggregates throughout the simulations, suggesting that dissociation of peptides from the disordered aggregates was an obligatory step toward the formation of ordered oligomers. Although 95% of peptides formed oligomers and 44% were in beta-extended conformations, only 16% of peptides formed multistrand beta-sheets. The disordered aggregates were mainly stabilized by hydrophobic interactions while cross-strand main-chain hydrogen bonds manifested the ordered oligomers. The transition to the beta-extended conformation was mildly cooperative due to short-range interactions between beta-extended peptides. Taken together, we propose that the role of hydrophobic interaction in the early stage of aggregation is to promote disordered aggregates and disfavor the formation of ordered nuclei and dissociation of the disordered oligomers could be the rate-limiting step at the initiation stage.


Sexual violence, marital guidance, and Victorian bodies: an aesthesiology.
This essay examines some of the emotional rules, encoded in grammars of representation and framed within law and prescriptive marital advice literature, regarding the expression of male sexual aggressivity within the bedroom. Despite the general Victorian idealization of marriage, many wives suffered physical and sexual abuse at the hands of their husbands, marital rape drawing particular attention from early feminists, psychologists, physicians, and evolutionary physiologists. In the 1870s, a belief that unrestrained sexual license was a symptom of degeneration led these commentators to consider marital rape particularly harmful to husbands. By the turn of the century, however, the focus of this harm had nominally shifted to women, who might become frigid if forced to submit to sex--a problem for wives but for husbands as well. As sexology and psychology gained greater influence, couples came to rely on the emotion-talk of commentators to negotiate mutually agreeable bedroom activity.


Obstructive sleep apnea: clinical and diagnostic features.
Obstructive sleep apnea (OSA) is an increasingly common disorder. It is characterized by frequent episodes of airway obstruction associated with a reduced caliber of the upper airway and is vulnerable to further narrowing and collapse. Acute and repetitive effects of apnea and hypopnea include oxygen desaturation, reduction in intrathoracic pressure, excessive daytime sleepiness, impaired executive function and central nervous system arousals. The apnea-hypopnea index and respiratory distress index help quantify the severity of the condition. The condition is associated with several clinical symptoms of which daytime sleepiness is considered the cardinal symptom. Obesity is one of the major predisposing factors. Three types of apneas have been recognized -obstructive, central and mixed; OSA is the commonest. This review will cover aspects of their radiologic features, diagnosis and management.


Hydrolysis of the amorphous cellulose in cotton-based paper.
Hydrolysis of cellulose in Whatman no. 42 cotton-based paper was studied using gel permeation chromatography (GPC), electrospray ionization-mass spectrometry (ESI-MS), and uniaxial tensile testing to understand the course and kinetics of the reaction. GPC results suggested that scission reactions passed through three stages. Additionally, the evolution of soluble oligomers in the ESI-MS data and the steady course of strength loss showed that the hydrolysis reaction occurred at a constant rate. These findings are explained with a more detailed description of the cellulose hydrolysis, which includes multiple chain scissions on amorphous segments. The breaks occur with increasing frequency near the ends of amorphous segments, where chains protrude from crystalline domains. Oligomers unattached to crystalline domains are eventually created. Late-stage reactions near the ends of amorphous segments produce a kinetic behavior that falsely suggests that hydrolysis had ceased. Monte Carlo simulations of cellulose degradation corroborated the experimental findings.


Tolerability and Muscle Activity of Core Muscle Exercises in Chronic Low-back Pain.
Most of the studies evaluating core muscle activity during exercises have been conducted with healthy participants. The objective of this study was to compare core muscle activity and tolerability of a variety of dynamic and isometric exercises in patients with non-specific low back pain (NSLBP). 13 outpatients (average age 52 years; all with standing or walking work in their current or latest job) performed 3 consecutive repetitions at 15-repetition maximum during different exercises in random order. Surface electromyography was recorded for the rectus abdominis; external oblique and lumbar erector spinae. Patients rated tolerability of each exercise on a 5-point scale. The front plank with brace; front plank and modified curl-up can be considered the most effective exercises in activating the rectus abdominis; with a median normalized EMG (nEMG) value of 48% (34-61%), 46% (26-61%) and 50% (28-65%), respectively. The front plank with brace can be considered the most effective exercise in activating the external oblique; with a nEMG of 77% (60-97%). The squat and bird-dog exercises are especially effective in activing the lumbar erector spinae; with nEMG of 40% (24-87%) and 29% (27-46%), respectively. All the exercises were well tolerated; except for the lateral plank that was mostly non-tolerated. In conclusion; the present study provides a variety of dynamic and isometric exercises; where muscle activity values and tolerability can be used as guide to design evidence-based exercise programs for outpatients with NSCLBP.


SR-XRD and SR-FTIR study of the alteration of silver foils in medieval paintings.
Altarpieces and polychrome carved wood from the fifteenth century AD usually exhibit golden and silvery areas by the application of a very thin foil of metal. The metal foils were normally protected from the atmosphere by a varnish or resin which maybe either preserved or absent. Moreover, they were glued to the background surface by adhesive substances (egg yolk, drying oil or animal glue). The high proportion of the glueing substances often renders the development of reaction compounds. With time, silver alters blacken or simply disappear completely. In this paper, we study the alterations to metal foils from a selection of fifteenth century artworks showing different glueing agents, organic coatings and several degrees of conservation of the organic coatings and metal leafs. The submillimetric layered structure and the high variability and low amount of most of the compounds present in the different layers, as well as their differing nature (organic and inorganic) make the use of micron-sensitive high-resolution techniques essential for their study. In particular, the high resolution, high brilliance and small footprint renders synchrotron radiation most adequate for their study. SR-XRD was performed to identify the reaction compounds formed in the different layers; μFTIR was used at to identify the silver protecting organic coatings, the metal foil glueing layers and the corresponding reaction compounds. The results obtained suggest that atmospheric corrosion is the dominant mechanism, and therefore that the degree of corrosion of the metal foils is mainly related to the conservation state of the protecting coatings.


The coming of age of the mitochondria-ER contact: a matter of thickness.
The sites of near-contact between the mitochondrion and the endoplasmic reticulum (ER) have earned a lot of attention due to their key role in the maintenance of lipid and calcium (Ca(2+)) homeostasis, in the initiation of autophagy and mitochondrial division, and in sensing metabolic shifts. At these sites, typically called MAMs (mitochondria-associated ER membranes) or MERCs (mitochondria-ER contacts), the organelles juxtapose at a distance that can range from ~10 to ~50 nm. The multifunctional role of this subcellular compartment is puzzling; further, recent studies have shown that mitochondria-ER contacts are highly plastic structures that remodel upon metabolic transitions and that their activity in controlling lipid homeostasis could be involved in Alzheimer's disease pathogenesis. This review aims at integrating the functions of this subcellular compartment to its most characterizing and unexplored structural parameter, their 'thickness': that is, the width of the cleft that separates the cytosolic face of the outer mitochondrial membrane from that of the ER. We describe and discuss the reasons why the thickness of a MERC should be considered a regulated structural parameter of the cell that defines and controls its function. Further, we propose a MERC classification that will help organize the expanding field of MERCs biology and of their role in cell physiology and human disease.


Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3.
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.


The impact of brief high-intensity exercise on blood glucose levels.
Moderate-intensity exercise improves blood glucose (BG), but most people fail to achieve the required exercise volume. High-intensity exercise (HIE) protocols vary. Maximal cycle ergometer sprint interval training typically requires only 2.5 minutes of HIE and a total training time commitment (including rest and warm up) of 25 minutes per session. The effect of brief high-intensity exercise on blood glucose levels of people with and without diabetes is reviewed. HIE (≥80% maximal oxygen uptake, VO2max) studies with ≤15 minutes HIE per session were reviewed. Six studies of nondiabetics (51 males, 14 females) requiring 7.5 to 20 minutes/week of HIE are reviewed. Two weeks of sprint interval training increased insulin sensitivity up to 3 days postintervention. Twelve weeks near maximal interval running (total exercise time 40 minutes/week) improved BG to a similar extent as running at 65% VO2max for 150 minutes/week. Eight studies of diabetics (41 type 1 and 22 type 2 subjects) were reviewed. Six were of a single exercise session with 44 seconds to 13 minutes of HIE, and the others were 2 and 7 weeks duration with 20 and 2 minutes/week HIE, respectively. With type 1 and 2 diabetes, BG was generally higher during and up to 2 hours after HIE compared to controls. With type 1 diabetics, BG decreased from midnight to 6 AM following HIE the previous morning. With type 2 diabetes, a single session improved postprandial BG for 24 hours, while a 2-week program reduced the average BG by 13% at 48 to 72 hours after exercise and also increased GLUT4 by 369%. Very brief HIE improves BG 1 to 3 days postexercise in both diabetics and non-diabetics. HIE is unlikely to cause hypoglycemia during and immediately after exercise. Larger and longer randomized studies are needed to determine the safety, acceptability, long-term efficacy, and optimal exercise intensity and duration.


Bacteriologically confirmed pulmonary tuberculosis in childhood. Clinical and radiological features.
Over a 4-year period 185 cases of pulmonary tuberculosis in children were confirmed by culture of Mycobacterium tuberculosis, usually from gastric aspirate. The majority of cases occurred in boys (62%) and the younger age groups were more commonly affected--26% of patients were less than 1 year old and 65% less than 3 years of age. At the time of presentation 40% of the 151 children tested had a negative tuberculin test. A chest radiograph was available in 136 cases. The commonest changes seen were lymphadenopathy (63%) and segmental lesions (56%). The latter affected mainly the right lung and in particular the right middle lobe. Cavitating tuberculous disease was present in 19 children, including 5 aged less than 1 year.


Enhancing optoacoustic mesoscopy through calibration-based iterative reconstruction.
Optoacoustic mesoscopy combines rich optical absorption contrast with high spatial resolution at tissue depths beyond reach for microscopic techniques employing focused light excitation. The mesoscopic imaging performance is commonly hindered by the use of inaccurate delay-and-sum reconstruction approaches and idealized modeling assumptions. In principle, image reconstruction performance could be enhanced by simulating the optoacoustic signal generation, propagation, and detection path. However, for most realistic experimental scenarios, the underlying total impulse response (TIR) cannot be accurately modelled. Here we propose to capture the TIR by scanning of a sub-resolution sized absorber. Significant improvement of spatial resolution and depth uniformity is demonstrated over 3 mm range, outperforming delay-and-sum and model-based reconstruction implementations. Reconstruction performance is validated by imaging subcutaneous murine vasculature and human skin in vivo. The proposed experimental calibration and reconstruction paradigm facilitates quantitative inversions while averting complex physics-based simulations. It can readily be applied to other imaging modalities employing TIR-based reconstructions.


Effects of Circuit Resistance Training on Body Composition, Strength, and Cardiorespiratory Fitness in Middle-Aged and Older Women: A Systematic Review and Meta-Analysis.
A systematic review with meta-analysis was conducted to evaluate the effects of circuit resistance training (CRT) on cardiorespiratory fitness, strength, and body composition in middle-aged and older women. Sixteen studies were included in the meta-analysis. The CRT interventions led to a significant decrease in weight, body mass index, and fat mass along with an increase in muscle mass. Significant differences were found in the fat mass and a trend to develop muscle mass when compared with the control group. CRT led to a significant increase in VO2max, walking endurance, and time to exhaustion; likewise, significant differences were observed when compared with the control group. CRT had a moderate and large favorable effect on arm, trunk, and lower limb strength. Furthermore, the increases in strength observed in the CRT were significantly greater than the changes observed in the control group. In middle-aged and older women, CRT improved cardiorespiratory fitness and strength and optimized body composition.


Gap junctional intercellular communication in bovine corneal endothelial cells.
Gap junctions and/or paracrine mediators, such as ATP, mediate intercellular communication (IC) in non-excitable cells. This study investigates the contribution of gap junctions toward IC during propagation of Ca(2+) waves in cultured bovine corneal endothelial cells (BCEC) elicited by applying a point mechanical stimulus to a single cell in a confluent monolayer. Changes in [Ca(2+)](i) were visualized using the fluorescent dye Fluo-4. The area reached by the Ca(2+) wave, called the active area (AA), was determined as a measure of efficacy of IC. RT-PCR and Western blotting showed expression of Cx43, a major form of connexin, in BCEC. In scrape-loading (using lucifer yellow) and fluorescence recovery after photobleaching (FRAP; using carboxyfluorescein) protocols, significant dye transfer of the hydrophilic dyes was evident indicating functional gap junctional IC (GJIC) in BCEC. Gap27 (300 microM), a connexin mimetic peptide that blocks gap junctions formed by Cx43, reduced the fluorescence recovery in FRAP experiments by 19%. Gap27 also reduced the active area of the Ca(2+) wave induced by point mechanical stimulation from 73,689 microm(2) to 26,936 microm(2), implying that GJIC contribution to the spread of the wave is at least approximately 63%. Inhibitors of ATP-mediated paracrine IC (PIC), such as a combination of apyrase VI and apyrase VII (5U/ml each; exogenous ATPases), suramin (200 microM; P2Y antagonist), or Gap26 (300 microM; blocker of Cx43 hemichannels) reduced the active area by 91%, 67%, and 55%, respectively. Therefore, estimating the contribution of GJIC from the residual active area after PIC inhibition appears to suggest that GJIC contributes no more than approximately 9% towards the active area of the Ca(2+) wave. Gap27 did not affect the enhancement in active area induced by ARL-67156 (200 microM, ectonucleotidase inhibitor), ATP release induced by point mechanical stimulation, and zero [Ca(2+)](o)-induced lucifer yellow uptake, indicating that the peptide has no influence on PIC. Exposure to Gap27 in the presence of PIC inhibitors led to a significant further inhibition of the Ca(2+) wave. The finding that the residual active area after inhibition of PIC by apyrases was much smaller than the reduction of the active area by Gap27, provides evidence for interaction between GJIC and PIC. These findings together suggest that functional gap junctions are present in BCEC, that both GJIC and PIC contribute significantly to IC, and that the two pathways interact.


Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes.
Numerous studies of human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTL) have examined their ability to recognize B-cell lines expressing recombinant HIV-1 proteins, but relatively few data regarding the lysis of HIV-1-infected cells by CTL are available. We studied the ability of HIV-1-specific CTL clones of defined epitope specificity and HLA restriction to lyse infected CD4+ cells at serial time points following infection. CD4+ cell lines were acutely infected with HIV-1 IIIB at a high multiplicity of infection, and the kinetics of cell lysis were examined and compared with the kinetics of viral replication. Intracellular HIV-1 p24 expression was detected by 1 to 2 days after infection, reaching over 98% positive cells by day 4. Recognition of the infected cells by HLA A2- and B14-restricted CTL clones closely paralleled intracellular p24 expression and preceded peak virion production. The maximal levels of lysis with Gag-, reverse transcriptase-, and envelope-specific clones were different, however. The Gag- and envelope-specific clones lysed infected cells at levels equivalent to peptide-sensitized controls, whereas lysis by the reverse transcriptase-specific clones plateaued at a lower level. Peptide titration curves indicated that this effect was not due to differences in sensitivity to the cognate epitopes for the different clones. Although HIV-1 infection induced an approximately 50% decrease in class I HLA expression on the surface of infected cells, lysis by CTL clones was unaffected. These studies indicate that HIV-1-specific CTL can efficiently lyse HIV-1-infected CD4+ cells and suggest that the partial downregulation of class I molecules in infected cells does not significantly affect recognition by CTL.


Epigenetic Modification Prevents Excessive Wound Healing and Scar Formation After Glaucoma Filtration Surgery.
The purpose of this study was to determine the efficacy of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi), in prevention of excessive wound healing and scar formation in a rabbit model of glaucoma filtration surgery (GFS). A rabbit model of GFS was used. Rabbits that underwent GFS received balanced salt solution, or SAHA (50 μM), or mitomycin C (0.02%). Clinical scores of IOP, bleb vascularity, and slit-lamp examination were performed. On postoperative day 14, rabbits were killed and the bleb tissues were collected for evaluation of tissue fibrosis with hematoxylin and eosin, Masson trichrome, α-smooth muscle actin (αSMA), and F-actin staining. Furthermore, SAHA-mediated acetylation of histones in corneal fibroblasts and conjunctiva were determined by Western blot analysis. Suberoylanilide hydroxamic acid treatment after GFS showed no signs of edema, corneal opacity, endophthalmitis, or cataract formation. Morphometric analysis of SAHA-treated eyes showed higher bleb length (P < 0.001), bleb area (P < 0.05), lower IOP (P < 0.01), and decreased vascularity compared to control. Furthermore, SAHA treatment showed significantly reduced levels of αSMA (P < 0.001), F-actin (P < 0.01), and collagen deposition (P < 0.05) at the sclerotomy site. In addition, SAHA treatment increased the acetylation status of H3 and H4 histones in corneal fibroblasts and conjunctiva. This study demonstrates that HDAC inhibition is an attractive pharmacologic target to modulate GFS wound healing, and SAHA, an HDACi, can be a useful adjunct to improve the GFS outcome.


Intensive case management as a jail diversion program for people with a serious mental illness: a review of the literature.
This article reviews the research on intensive case management (ICM) programs as a jail diversion intervention for people with a serious mental illness (SMI). The review includes two types of ICM programs: (a) general ICM programs that included an assessment of arrests and incarceration rates for people with an SMI and (b) ICM programs specifically implemented as a component of a jail diversion intervention for people with an SMI. Results indicate that general ICM programs (19) rarely led to reductions in jail or arrest rates over time, and these rates were similar to those found in standard mental health services. General ICM programs that included an integrated addiction treatment component (8) had mixed results but a trend toward reductions in rates of arrests and incarceration over time for individuals with an SMI and a co-occurring substance use disorder. Results were mixed for jail diversion interventions with an ICM program, but most ICM programs (8) led to significant reductions in arrests and incarcerations over time. Specific elements of effective ICM jail diversion programs are discussed.


Different sensitivity of mitochondrial and cytosolic monoamine oxidases to in vivo but not in vitro inhibition by specific irreversible inhibitors.
The sensitivity of mitochondrial and cytosolic monoamine oxidase (MAO) activities to inhibition by specific irreversible inhibitors was investigated. There were no significant differences in the sensitivity of MAO A and MAO B activities of these fractions to selective inhibitors. However, in vivo administration of pargyline caused a much more potent inhibition of cytosolic MAO than the mitochondrial enzymes. This suggests that cytosolic MAO activity does not represent an artifact (e.g. a product of proteolytic degradation) appearing after tissue homogenisation. The higher sensitivity of cytosolic MAO to inhibitors also points to different routes for pargyline to inhibit MAO in these subcellular fractions.


Prevalence of phylogroups and O25/ST131 in susceptible and extended-spectrum β-lactamase-producing Escherichia coli isolates, the Netherlands.
To assess the distribution of phylogroups and O25/ST131 in the Netherlands, we performed a real-time polymerase chain reaction (PCR) on a collection of 108 wild-type Escherichia coli (WT-EC) and 134 extended-spectrum β-lactamase-producing E. coli (ESBL-EC). Phylogroup B2 was predominant, but ESBL-EC were less likely to belong to this phylogroup (48.5%) than were WT-EC (66.7%; p = 0.005). In WT-EC, phylogroups B2 and D seem to be more virulent, having a higher prevalence among midstream urine isolates and blood culture isolates, than in catheter-related urine isolates (83.3% and 87.9% vs. 61.9%; p 0.048). O25/ST131 is associated with ESBL production, being almost absent among phylogroup B2 WT-EC (61.5% vs. 5.6%; p < 0.001).


Australian, Irish and Swedish women's perceptions of what assisted them to breastfeed for six months: exploratory design using critical incident technique.
Breastfeeding initiation rates in some developed countries are high (98 % in Sweden and 96 % in Australia) whereas in others, they are not as favourable (46 % to 55 % in Ireland). Although the World Health Organization recommends exclusively breastfeeding for six months, 15 % of Australian women, 11 % of Swedish women and less than 7 % of Irish women achieve this goal. Awareness of what women in different countries perceive as essential breastfeeding support is a gap in our knowledge. Our aim was to explore Australian, Irish and Swedish women's perceptions of what assisted them to continue breastfeeding for six months. An exploratory design using critical incident techniques was used. Recruitment occurred through advertisements in local newspapers and on social networking platforms. Initial sampling was purposive, followed by snowball sampling. Telephone interviews were conducted with 64 Irish, 139 Swedish and 153 Australian women who responded to one question "what has assisted you to continue breastfeeding for at least six months?" Content analysis was conducted and common categories determined to allow comparison of frequencies and priority ranking. Categories reflected the individual mother, her inner social network, her outer social network (informal support either face to face or online), and societal support (health professionals, work environment and breastfeeding being regarded as the cultural norm). Categories ranked in the top five across the three countries were 'informal face to face support' and 'maternal determination'. Swedish and Australian women ranked "health professional support" higher (first and third respectively) than Irish women who ranked 'informal online support' as second compared to ninth and tenth for Swedish and Australian women. The support required to assist breastfeeding women is complex and multi-faceted. Although common international categories were revealed, the ranking of these supportive categories varied. We must recognize how the cultural context of breastfeeding support can vary for women in differing countries and acknowledge the resourcefulness of women who embrace innovations such as social media where face to face formal and informal support are not as accessible.


Renormalized dispersion relations of β-Fermi-Pasta-Ulam chains in equilibrium and nonequilibrium states.
We study the nonlinear dispersive characteristics in β-Fermi-Pasta-Ulam (FPU) chains in both thermal equilibrium and nonequilibrium steady state. By applying a multiple scale analysis to the FPU chain, we analyze the contribution of the trivial and nontrivial resonance to the renormalization of the dispersion relation. Our results show that the contribution of the nontrivial resonance remains significant to the renormalization, in particular, in strongly nonlinear regimes. We contrast our results with the dispersion relations obtained from the Zwanzig-Mori formalism and random phase approximation to further illustrate the role of resonances. Surprisingly, these theoretical dispersion relations can be generalized to describe dispersive characteristics well at the nonequilibrium steady state of the FPU chain with driving-damping in real space. Through numerical simulation, we confirm that the theoretical renormalized dispersion relations are valid for a wide range of nonlinearities in thermal equilibrium as well as in nonequilibrium steady state. We further show that the dispersive characteristics persist in nonequilibrium steady state driven-damped in Fourier space.


Fatigue, anxiety, depression and sleep quality in patients undergoing haemodialysis.
Patients undergoing haemodialysis may experience troubling symptoms such as fatigue, anxiety, depression and sleep quality, which may affect their quality of life. The main objective of this study is to determine the prevalence of fatigue, anxiety, depression and sleep quality among patients receiving haemodialysis during the coronavirus disease 2019 (COVID-19) pandemic, and to explore the contributing predictors. A cross-sectional and descriptive correlational design using Qualtrics software was performed. Data were collected using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F), the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI). Logistic regression analyses were used to explore the predictors that were associated with fatigue, anxiety, depression and sleep quality. Of the 123 patients undergoing haemodialysis who participated, 53.7% (n = 66) reported fatigue, 43.9% (n = 54) reported anxiety, 33.3% (n = 41) reported depression and 56.9% (n = 70) reported poor sleep. Fatigue, anxiety and sleep quality (P < .05) were significantly associated with being female, and whether family members or relatives were suspected or confirmed with COVID-19. Logistic regression showed that being within the age group 31-40, having a secondary education level, anxiety, depression and sleep quality were the main predictors affecting the fatigue group. Fatigue, anxiety, depression and sleep quality are significant problems for patients receiving haemodialysis during the COVID-19 pandemic. Appropriate interventions to monitor and reduce fatigue, psychological problems and sleep quality amongst these patients are needed. This can help to strengthen preparations for responding to possible future outbreaks or pandemics of infectious diseases for patients receiving haemodialysis.


Contralateral interhemispheric, transfalcine approach with asleep motor mapping for parasagittal lesions near the medial precentral gyrus.
The contralateral interhemispheric approach has several advantages for approaching parasagittal lesions, including lesions involving or approaching the medial precentral gyrus. Supplementing the interhemispheric approach with asleep motor mapping is useful for confirming the location of the corticospinal tracts from the contralateral transfalcine corridor and identifying subcortical motor fibers at the deep aspect of the resection cavity. The authors describe the contralateral interhemispheric, transfalcine approach with asleep motor mapping to resect a parasagittal metastatic lesion involving the medial precentral gyrus. The video can be found here: https://youtu.be/L-fJ6m5kOWs .


A bleomycin/ifosfamide/cisplatin regimen exhibits poor activity against persistent or recurrent squamous gynecologic cancers.
Persistent or recurrent squamous malignancies of the female genital tract are usually incurable by conventional therapy, and results of single agent chemotherapy have been disappointing. We undertook this study to confirm a previously reported response rate of 69%, using a regimen of bleomycin 30U, ifosfamide 5g/m2 with mesna 6g/m2, and cisplatin 50 mg/m2 (BIP) for recurrent cervical cancer. This regimen was used to treat persistent or recurrent squamous cancers in women with cervical cancer (n = 11), vaginal cancer (n = 1) and vulvar cancer (n = 1). Results were reviewed retrospectively and toxicities graded according to the criteria of the Gynecologic Oncology Group. No complete responses were seen. One patient had a partial response (10%, 95% confidence interval 0-28%). Five patients (50%), exhibiting stable disease during therapy with BIP, progressed after cessation of therapy. Of 9 women with symptoms after one cycle. Significant toxicities included neutropenic fever (3 grade 3, 3 grade 4), emesis (1 grade 3), confusion (2 grade 4), vaginal bleeding (2 grade 3), and renal failure (1 grade 3). Eight patients were transfused with a total of 28 units of red cells. After 23 months of follow-up, all patients were dead of disease. Mean survival was 10 months. Toxicity associated with this regimen can be significant, and results appear no better than those reported with single agent therapy.


Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency.
Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755-62. ©2017 AACR.


Identification of serum proteins and multivariate models for diagnosis and therapeutic monitoring of lung cancer.
Lung cancer is one of the most prevalent cancers and has very poor treatment outcome. Biomarkers useful for screening and assessing early therapeutic response may significantly improve the therapeutic outcome but are still lacking. In this study, serum samples from 218 non-small cell lung cancer (NSCLC) patients, 34 small cell lung cancer (SCLC) patients and 171 matched healthy controls from China were analyzed for 11 proteins using the Luminex multiplex assay. Eight of the 11 proteins (OPN, SAA, CRP, CYFRA21.1, CEA, NSE, AGP and HGF) are significantly elevated in NSCLC and SCLC (p = 10-5-10-59). At the individual protein level, OPN has the best diagnostic value for NSCLC (AUC = 0.92), two acute phase proteins (SAA and CRP) have AUC near 0.83, while CEA and CYFRA21.1 also possess good AUC (0.81 and 0.77, respectively). More importantly, several three-protein combinations that contain OPN and CEA plus one of four proteins (CRP, SAA, CYFRA21.1 or NSE) have excellent diagnostic potential for NSCLC (AUC = 0.96). Four proteins (CYFRA21.1, CRP, SAA and NSE) are severely reduced and three proteins (OPN, MIF and NSE) are moderately decreased after platinum-based chemotherapy. Therapeutic response index (TRI) computed with 3-5 proteins suggests that approximately 25% of the NSCLC patients respond well to the therapy and TRI is significantly correlated with pre-treatment protein levels. Our data suggest that therapeutic response in NSCLC patients can be effectively measured but personalized biomarkers may be needed to monitor different subsets of patients.


Tulsi - Ocimum sanctum: A herb for all reasons.
The predominant cause of global morbidity and mortality is lifestyle-related chronic diseases, many of which can be addressed through Ayurveda with its focus on healthy lifestyle practices and regular consumption of adaptogenic herbs. Of all the herbs used within Ayurveda, tulsi (Ocimum sanctum Linn) is preeminent, and scientific research is now confirming its beneficial effects. There is mounting evidence that tulsi can address physical, chemical, metabolic and psychological stress through a unique combination of pharmacological actions. Tulsi has been found to protect organs and tissues against chemical stress from industrial pollutants and heavy metals, and physical stress from prolonged physical exertion, ischemia, physical restraint and exposure to cold and excessive noise. Tulsi has also been shown to counter metabolic stress through normalization of blood glucose, blood pressure and lipid levels, and psychological stress through positive effects on memory and cognitive function and through its anxiolytic and anti-depressant properties. Tulsi's broad-spectrum antimicrobial activity, which includes activity against a range of human and animal pathogens, suggests it can be used as a hand sanitizer, mouthwash and water purifier as well as in animal rearing, wound healing, the preservation of food stuffs and herbal raw materials and traveler's health. Cultivation of tulsi plants has both spiritual and practical significance that connects the grower to the creative powers of nature, and organic cultivation offers solutions for food security, rural poverty, hunger, environmental degradation and climate change. The use of tulsi in daily rituals is a testament to Ayurvedic wisdom and provides an example of ancient knowledge offering solutions to modern problems.


How sources of health information relate to knowledge and use of cancer screening exams.
Utilization of many screening procedures to detect cancer in early stages remains low. In order to design more effective strategies to increase utilization of these tests, we assessed the role and relative importance of different information sources on knowledge and use of cancer screening exams. Where individuals get useful information about disease prevention, and the relationship of information sources to cancer screening knowledge and behavior are reported using data from the 1987 National Health Interview Survey. Results indicate that physicians are perceived as important sources of information on how to prevent illness. However, persons who use print media as their most useful source of information are significantly more likely to have heard of cancer screening procedures than those who rely on the doctor as the source. Those who rely on electronic media tend to be less knowledgeable of all screening procedures examined. A strong and consistent association between doctor as the most useful source of information and actually having received the procedure was found. These results suggest that knowledge may not necessarily be a prerequisite to screening and indicate that reliance on the physician to recommend cancer screening may be critical in utilization of these services.


Pathogenicity of nodavirus strains from striped jack Pseudocaranx dentex and Atlantic halibut Hippoglossus hippoglossus, studied by waterborne challenge of yolk-sac larvae of both teleost species.
The present study shows that differences in pathogenicity exist among fish nodavirus strains. In challenge trials, a Japanese strain (SJ93Nag) was highly virulent to larvae of the striped jack Pseudocaranx dentex but replication was not detected in larvae of Atlantic halibut Hippoglossus hippoglossus at 6 degrees C. Conversely, a Norwegian nodavirus strain (AH95NorA) that was highly virulent to the Atlantic halibut larvae did not replicate in striped jack larvae at 20 degrees C. Occurrence of the disease viral encephalopathy and retinopathy (VER) and cumulative mortality were significantly different in the 2 species when challenged with the 2 nodavirus strains. The presence of nodavirus in nervous tissue was monitored by immunohistochemical methods. Our results support the view that the genetic diversity among nodavirus strains reflects the existence of different viral phenotypes which may be adapted to infect different host species and/or for replicating at different temperatures. Fish nodaviruses represent surveyable pathogens well suited for studying the relation between viral genotypic and phenotypic properties such as host specificity, temperature optima, neuroinvasiveness and neurovirulence.


Phenotypic characterization of HIV-specific CD8+ T cells during early and chronic infant HIV-1 infection.
Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-γ-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.


Accuracy of evidence-based criteria for identifying an incident hip fracture in the absence of the date of injury: a retrospective database study.
Hospital discharge data (HDD) in many health systems do not capture the date of injury (DOI); the absence of this date hinders researchers' ability to distinguish repeat from incident injury admissions. Various approaches using somewhat arbitrary criteria have been explored to increase the accuracy of incident injury identification. However, these approaches have not been validated against a data source which contains DOI. The aim of this study was to determine the accuracy of evidence-based criteria for identifying fall-related incident hip fractures in the absence of DOI using HDD containing DOI as the reference standard. Retrospective database study. New Zealand. 8761 patients aged 65+ years admitted for fall-related hip fracture between 1 July 2005 and 30 June 2008, inclusive. We defined person-identifying HDD containing DOI as the reference standard and calculated measures of the accuracy of evidence-based criteria for identifying fall-related incident hip fractures from HDD not containing DOI. The criteria were principal diagnosis of hip fracture, mechanism of injury indicating a fall, admission type emergency, admission source other than a transfer and presence of hip operation code(s). For a subsequent fall-related hip fracture, additional criteria were time between successive hip fractures ≥120 days, and all external cause-of-injury codes being different to those for the previous hip fracture. The sensitivity and specificity of the criteria for identifying fall-related incident hip fractures from data not containing DOI were 96.7% and 99.3%, respectively, compared with the reference standard. The application of these criteria resulted in a slight underestimation of the percentage of patients with multiple hip fractures. Although it is preferable to have DOI; this study demonstrates that evidence-based criteria can be used to reliably identify fall-related incident hip fractures from the person-identifying HDD when DOI is unavailable.


Resveratrol protects human endothelium from H(2)O(2)-induced oxidative stress and senescence via SirT1 activation.
Silencing information regulator (SirT1), a NAD-dependent histone deacetylase, is an essential mediator of longevity in normal cells by calorie restriction. SirT1 has many biological functions, including transcription regulation, cell differentiation inhibition, cell cycle regulation, and anti-apoptosis. Resveratrol (RV)-induced SirT1 activation also improves endothelial dysfunction and suppresses vascular inflammation. In this study, we investigated the roles of RV-induced SirT1 activation in endothelial cells under oxidative stress. SirT1 mRNA expression levels were examined in the endothelium layer (endothelial cells) of cardiac coronary vessels from patients receiving coronary artery bypass graft surgery (CABG) surgery and aged rats using reverse transcriptase polymerase chain reaction (RT-PCR). To further explore the effect of SirT1 activation on oxidative stress-induced aging, senescence-associated β-galactosidase (SA-β-gal) expression in RV-treated human umbilical vein endothelial cells (HUVECs) with or without H(2)O(2) treatment was evaluated. SirT1 expression was decreased in aged and atherosclerotic vessels in vivo, and significantly reduced in endothelial cells purified from vessel tissues. Furthermore, SirT1 levels were dose-dependently increased in RV-treated HUVECs. The SA-β gal assay showed that RV inhibited the senescent phenotype of H(2)O(2)-treated HUVECs. Reactive oxygen species (ROS) production and the percentage of cells positive for SA-β gal were significantly increased in siRNA-SirT1 (knockdown of SirT1 expression)-treated HUVEC cells. Importantly, the treatment effect of RV was significantly abolished in the oxidative effects of H(2)O(2)-treated HUVECs by siRNA-SirT1. Our data suggested that SirT1 could be a crucial factor involved in the endothelial cells of atherosclerotic CAGB patients and aging rats. RV is a potential candidate for preventing oxidative stress-induced aging in endothelial cells. RV may also prevent ROS-induced damage via increased endothelial SirT1 expression.


A case of probable piperacillin/tazobactam-induced bone marrow suppression in a pregnant woman.
Piperacillin/tazobactam is a bacteriolytic combined antibiotic. The least common reported adverse reactions of piperacillin/tazobactam are haematological reactions (<1%). The use of piperacillin/tazobactam during pregnancy is considered to be moderately safe (pregnancy category B) for the human embryo-foetus. This is a case of a pregnant patient (22 weeks of gestation) who was admitted to the Women's Hospital, Doha, Qatar and was treated for preterm premature rupture of membrane with erythromycin for 10 days. Afterwards, she was treated with piperacillin/tazobactam for asymptomatic urinary tract infection (pseudomonas species). After 15 days, she developed fever, leucopenia, neutropenia and thrombocytopenia. These adverse reactions were reversed after the discontinuation of piperacillin/tazobactam combination. In Qatar and worldwide, there are few reported cases regarding bone marrow suppression or fever induced by piperacillin/tazobactam in general and during pregnancy. Using the Naranjo Adverse Drug Reaction Probability scales, the score was found to be 8, representing a probable adverse drug reaction.


Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.
To determine factors associated with COVID-19-related death in people with rheumatic diseases. Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.


Fluid control in multichannel structures by electrocapillary pressure.
We demonstrate control of fluid motion in three-dimensional structures with thousands of microchannels. Fluids are manipulated via an electrocapillary pressure, originating from electrostatic control of the solid/fluid interfacial tension in the microchannels. Reversible fluid displacement has been achieved for all channel orientations with respect to gravity. The velocities of several centimeters per second are nearly two orders of magnitude higher than the velocities demonstrated by other electrofluidic actuation principles.


Synthesis and evaluation of analogues of N-phthaloyl-l-tryptophan (RG108) as inhibitors of DNA methyltransferase 1.
DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.


The Healthy People 2010 smoking prevalence and tobacco control objectives: results from the SimSmoke tobacco control policy simulation model (United States).
Healthy People 2010 (HP2010) set a goal of reducing the adult smoking prevalence to 12% by 2010. Smoking prevalence rates do not appear to be declining at or near the rate targeted in the HP2010 goals. The purpose of this paper is to examine the attainability of HP2010 smoking prevalence objectives through the stricter tobacco control policies suggested in HP2010. A tested dynamic simulation model of smoking trends, known as SimSmoke, is applied. Smoking prevalence evolves over time through initiation and cessation, behaviors which are in turned influenced by tobacco control policies. We consider the effect of changes in taxes/prices, clean air laws, media campaigns, cessation programs and youth access policies on projected smoking prevalence over the period 2003-2020, focusing on the levels in 2010. The SimSmoke model projects that the aging of older cohorts and the impact of policies in years prior to 2004 will yield a reduction in smoking rates to 18.4% by 2010, which is substantially above the 2010 target of 12%. When policies similar to the HP2010 tobacco control policy objectives are implemented, SimSmoke projects that smoking rates could be reduced to 16.1%. Further reductions might be realized by increasing the tax rate by $1.00. The SimSmoke model suggests that the HP2010 smoking prevalence objective is unlikely to be attained. Although we are unlikely to reach the goals by meeting the HP2010 policy objectives, they could get us much closer to the goal. Emphasis should be placed on meeting the tax, clean air, media/comprehensive campaigns, and cessation treatment objectives.


Photosystem I is indispensable for photoautotrophic growth, CO2 fixation, and H2 photoproduction in Chlamydomonas reinhardtii.
Certain Chlamydomonas reinhardtii mutants deficient in photosystem I due to defects in psaA mRNA maturation have been reported to be capable of CO2 fixation, H2 photoevolution, and photoautotrophic growth (Greenbaum, E., Lee, J. W., Tevault, C. V., Blankinship, S. L. , and Mets, L. J. (1995) Nature 376, 438-441 and Lee, J. W., Tevault, C. V., Owens, T. G.; Greenbaum, E. (1996) Science 273, 364-367). We have generated deletions of photosystem I core subunits in both wild type and these mutant strains and have analyzed their abilities to grow photoautotrophically, to fix CO2, and to photoevolve O2 or H2 (using mass spectrometry) as well as their photosystem I content (using immunological and spectroscopic analyses). We find no instance of a strain that can perform photosynthesis in the absence of photosystem I. The F8 strain harbored a small amount of photosystem I, and it could fix CO2 and grow slowly, but it lost these abilities after deletion of either psaA or psaC; these activities could be restored to the F8-psaADelta mutant by reintroduction of psaA. We observed limited O2 photoevolution in mutants lacking photosystem I; use of 18O2 indicated that this O2 evolution is coupled to O2 uptake (i.e. respiration) rather than CO2 fixation or H2 evolution. We conclude that the reported instances of CO2 fixation, H2 photoevolution, and photoautotrophic growth of photosystem I-deficient mutants result from the presence of unrecognized photosystem I.


Available web-based dental implants information for patients. How good is it?
Massive use of the Internet for health issues has raised concerns about the quality of the information available and about consumers' ability to tell "good" from "bad" information. To assess the quality of patient-addressed, dental implants-related websites in terms of reliability, accessibility, usability and readability. Two search engines (Google and Yahoo) were used in this study. The first 100 sites, as listed by each engine, were considered for the study. Each site was categorised and analysed for quality using the DISCERN and the LIDA instruments. The Flesch-Kinkaid Reading Grade Level (FKRGL) and the Flesh Reading Ease Score (FRES) were used to assess legibility. After applying the inclusion and exclusion criteria, 32 single websites entered the study. The median score for the DISCERN instrument (3 [2-3]) indicated serious or potentially important shortcoming in the quality of the information obtained. LIDA scores showed modest percentages for accessibility (79.36 [74.60-85.31]) and intermediate for usability (59.20 (50.46-68.51)) and reliability (55.55 [45.37-66.66]). Legibility indices reached scores within the range of difficult to read (FRES = 51.72 [38.70-55.27]); FKRGL = 12.76 [10.07-14.87]). Available e-health information on dental implants in English language is difficult to read for the average patient and poor in terms of quality.


In vivo RNA localization of I factor, a non-LTR retrotransposon, requires a cis-acting signal in ORF2 and ORF1 protein.
According to the current model of non-LTR retrotransposon (NLR) mobilization, co-expression of the RNA transposition intermediate, and the proteins it encodes (ORF1p and ORF2p), is a requisite for the formation of cytoplasmic ribonucleoprotein complexes which contain necessary elements to complete a retrotransposition cycle later in the nucleus. To understand these early processes of NLR mobilization, here we analyzed in vivo the protein and RNA expression patterns of the I factor, a model NLR in Drosophila. We show that ORF1p and I factor RNA, specifically produced during transposition, are co-expressed and tightly co-localize with a specific pattern (Loc+) exclusively in the cytoplasm of germ cells permissive for retrotransposition. Using an ORF2 mutated I factor, we show that ORF2p plays no role in the Loc+ patterning. With deletion derivatives of an I factor we define an RNA localization signal required to display the Loc+ pattern. Finally, by complementation experiments we show that ORF1p is necessary for the efficient localization of I factor RNA. Our data suggest that ORF1p is involved in proper folding and stabilization of I factor RNA for efficient targeting, through Loc+ patterning, to the nuclear neighborhood where downstream steps of the retrotransposition process occur.


A Flexible Model of Working Memory.
Working memory is fundamental to cognition, allowing one to hold information "in mind." A defining characteristic of working memory is its flexibility: we can hold anything in mind. However, typical models of working memory rely on finely tuned, content-specific attractors to persistently maintain neural activity and therefore do not allow for the flexibility observed in behavior. Here, we present a flexible model of working memory that maintains representations through random recurrent connections between two layers of neurons: a structured "sensory" layer and a randomly connected, unstructured layer. As the interactions are untuned with respect to the content being stored, the network maintains any arbitrary input. However, in our model, this flexibility comes at a cost: the random connections overlap, leading to interference between representations and limiting the memory capacity of the network. Additionally, our model captures several other key behavioral and neurophysiological characteristics of working memory.


Rapid clinical deterioration in an individual with Down syndrome.
A small percentage of adolescents and young adults with Down syndrome experience a rapid and unexplained deterioration in cognitive, adaptive, and behavioral functioning. Currently, there is no standardized work-up available to evaluate these patients or treat them. Their decline typically involves intellectual deterioration, a loss of skills of daily living, and prominent behavioral changes. Certain cases follow significant life events such as completion of secondary school with friends who proceed on to college or employment beyond the individual with DS. Others develop this condition seemingly unprovoked. Increased attention in the medical community to clinical deterioration in adolescents and young adults with Down syndrome could provide a framework for improved diagnosis, evaluation, and treatment. This report presents a young adult male with Down syndrome who experienced severe and unexplained clinical deterioration, highlighting specific challenges in the systematic evaluation and treatment of these patients. © 2016 Wiley Periodicals, Inc.


Single-base DNA discrimination via transverse ionic transport.
We suggest the discrimination of single DNA bases via transverse ionic transport, namely by detecting the ionic current that flows in a channel while a single-stranded DNA is driven through an intersecting nanochannel. Our all-atom molecular dynamics simulations indeed show that the ionic currents of the four bases are statistically distinct, thus offering another possible approach to sequencing DNA.


[Use of psychotropics drugs among students: prevalence and associated social factors].
To determine the prevalence of the heavy use of drugs among elementary and high school students in a sample of public and private schools, and to identify associated demographic, psychological, cultural and social factors. This report describes a cross-sectional study using an intention-type sampling technique that compared public schools in central and peripheral areas and private schools. An anonymous self-administered questionnaire was applied. The sample consisted of 2,287 elementary and high school students in the city of Campinas in 1998. Heavy use of drugs was defined as the use of drugs on 20 or more days during the 30 days preceding the survey (WHO, 1981). For the statistical analysis, polytomic logistic regression analysis (logit model) was utilized to identify factors that influenced this manner of using drugs. Heavy use of legal and illegal drugs was found as follows: alcohol (11.9%), tobacco (11.7%), marijuana (4.4%), solvents (1.8%), cocaine (1.4%), medications (1.1%) and ecstasy (0.7%). The heavy use of drugs was greatest among students at the city-center public school who had daytime jobs and studied in the evenings. These students were in the A and B socioeconomic classes and had had little religious education during childhood. Greater availability of cash and specific socialization patterns were identified as factors associated with the heavy use of drugs among students.


Smoking prevalence and knowledge of associated risks in adult attenders at day centres for people with learning disabilities.
Increased longevity among people with learning disabilities is accompanied by an increase in morbidity. A possible explanation is that living in the community and a move to greater independence may bring higher health risks through obesity and smoking. The study aimed to see if rates of smoking have increased from earlier published rates and to ascertain the awareness of the risks of smoking among people with learning disabilities. A total of 435 people attending four social services day centres in a large urban area were assisted to complete a questionnaire. Twenty-seven (6.2%) reported that they currently smoked. Those with mild disabilities were much more likely to smoke than those with more severe disabilities and they also reported smoking more heavily. For those with mild levels of learning disability, a higher than expected proportion living in hospital and staffed housing smoked, a lower proportion living with parents smoked but for those living independently the proportion who smoked was no higher than expected. Smokers were more knowledgeable about the risks than non-smokers even if the level of learning disability was controlled for. Only a third of smokers were concerned about the risks. The study provides no evidence that rates of smoking are increasing among people with learning disabilities nor that those living independently were more likely to smoke. Knowledge of health risks is poor across the group, but higher among the smokers who were unlikely to express concern about the risks. This may indicate that more support may be needed along with health education in this group.


Separating reflection components of textured surfaces using a single image.
In inhomogeneous objects, highlights are linear combinations of diffuse and specular reflection components. A number of methods have been proposed to separate or decompose these two components. To our knowledge, all methods that use a single input image require explicit color segmentation to deal with multicolored surfaces. Unfortunately, for complex textured images, current color segmentation algorithms are still problematic to segment correctly. Consequently, a method without explicit color segmentation becomes indispensable and this paper presents such a method. The method is based solely on colors, particularly chromaticity, without requiring any geometrical information. One of the basic ideas is to iteratively compare the intensity logarithmic differentiation of an input image and its specular-free image. A specular-free image is an image that has exactly the same geometrical profile as the diffuse component of the input image and that can be generated by shifting each pixel's intensity and maximum chromaticity nonlinearly. Unlike existing methods using a single image, all processes in the proposed method are done locally, involving a maximum of only two neighboring pixels. This local operation is useful for handling textured objects with complex multicolored scenes. Evaluations by comparison with the results of polarizing filters demonstrate the effectiveness of the proposed method.


Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNα-Dendritic Cells and Rituximab: a Phase I Clinical Trial.
This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab. Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients. Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences. These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.


The cheetah is depauperate in genetic variation.
A sample of 55 South African cheetahs (Acinonyx jubatus jubatus) from two geographically isolated populations in South Africa were found to be genetically monomorphic at each of 47 allozyme (allelic isozyme) loci. Two-dimensional gel electrophoresis of 155 abundant soluble proteins from cheetah fibroblasts also revealed a low frequency of polymorphism (average heterozygosity, 0.013). Both estimates are dramatically lower than levels of variation reported in other cats and mammals in general. The extreme monomorphism may be a consequence of a demographic contraction of the cheetah (a population bottleneck) in association with a reduced rate of increase in the recent natural history of this endangered species.


New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.