Assessment of apathy in neurological patients using the Apathy Motivation Index caregiver version.
Apathy is a common, disabling neuropsychiatric syndrome that occurs across many brain disorders and may be associated with diminished motivation in behavioural, cognitive, emotional and social domains. Assessment is complicated by the variability of symptoms across apathy domains and self-report from patients, which can be misleading due to their lack of insight. Independent evaluation by clinicians also has limitations though if it has to be performed with limited time. Caregiver reports are a viable alternative, but current assessments for them either do not distinguish between different apathy domains or are interview-based and take long to administer. In this study, we developed a brief caregiver questionnaire version of the recently developed Apathy Motivation Index (AMI), which is a self-report tool. We confirmed three apathy factors in this new caregiver measure (AMI-CG) that were also present in the AMI: Behavioural Activation, Emotional Sensitivity and Social Motivation. Furthermore, we validated the scores against more extensive caregiver interviews using the established Lillle apathy rating scale as well as patient self-reports of apathy, measures of depression, anhedonia, cognition, activities of daily living and caregiver burden across four different neurological conditions: Parkinson's disease, Alzheimer's disease, subjective cognitive impairment and limbic encephalitis. The AMI-CG showed good internal reliability, external validity and diagnostic accuracy. It also uncovered cases of social apathy overlooked by traditional instruments. Crucially, patients who under-rated their apathy compared to informants were more likely to have difficulties performing everyday activities and to be a greater burden to caregivers. The findings provide evidence for a multidimensional conceptualization of apathy and an instrument for efficient detection of apathy based on caregiver reports for use in clinical practice.


Nanomaterials at the neural interface.
Interfacing the nervous system with devices able to efficiently record or modulate the electrical activity of neuronal cells represents the underlying foundation of future theranostic applications in neurology and of current openings in neuroscience research. These devices, usually sensing cell activity via microelectrodes, should be characterized by safe working conditions in the biological milieu together with a well-controlled operation-life. The stable device/neuronal electrical coupling at the interface requires tight interactions between the electrode surface and the cell membrane. This neuro-electrode hybrid represents the hyphen between the soft nature of neural tissue, generating electrical signals via ion motions, and the rigid realm of microelectronics and medical devices, dealing with electrons in motion. Efficient integration of these entities is essential for monitoring, analyzing and controlling neuronal signaling but poses significant technological challenges. Improving the cell/electrode interaction and thus the interface performance requires novel engineering of (nano)materials: tuning at the nanoscale electrode's properties may lead to engineer interfacing probes that better camouflaged with their biological target. In this brief review, we highlight the most recent concepts in nanotechnologies and nanomaterials that might help reducing the mismatch between tissue and electrode, focusing on the device's mechanical properties and its biological integration with the tissue.


Radiation forces on a Rayleigh particle by highly focused partially coherent and radially polarized vortex beams.
The radiation force of highly focused partially coherent and radially polarized vortex beams on a Rayleigh particle is theoretically studied. The dependence of the radiation force on coherence lengths, beam widths, topological charges of incident vortex beams, and numerical apertures of an objective is analyzed. The transverse scattering force is also investigated. It is found that the azimuthal scattering force can produce torques with respect to the optical axis if the optical tweezers are constructed by the vortex beams carrying orbit angular momentum. The direction of the torque depends on the sign of the topological charge of vortex beams, and the magnitude of the torque increases with the increase of the value of the topological charge. A Rayleigh particle can revolve around the optical axis driven by the vortex beams.


Racial disparities in blood pressure control and treatment differences in a Medicaid population, North Carolina, 2005-2006.
Racial disparities in prevalence and control of high blood pressure are well-documented. We studied blood pressure control and interventions received during the course of a year in a sample of black and white Medicaid recipients with high blood pressure and examined patient, provider, and treatment characteristics as potential explanatory factors for racial disparities in blood pressure control. We retrospectively reviewed the charts of 2,078 black and 1,436 white North Carolina Medicaid recipients who had high blood pressure managed in primary care practices from July 2005 through June 2006. Documented provider responses to high blood pressure during office visits during the prior year were reviewed. Blacks were less likely than whites to have blood pressure at goal (43.6% compared with 50.9%, P = .001). Blacks above goal were more likely than whites above goal to have been prescribed 4 or more antihypertensive drug classes (24.7% compared with 13.4%, P < .001); to have had medication adjusted during the prior year (46.7% compared with 40.4%, P = .02); and to have a documented provider response to high blood pressure during office visits (35.7% compared with 30.0% of visits, P = .02). Many blacks (28.0%) and whites (34.3%) with blood pressure above goal had fewer than 2 antihypertensive drug classes prescribed. In this population with Medicaid coverage and access to primary care, blacks were less likely than whites to have their blood pressure controlled. Blacks received more frequent intervention and had greater use of combination antihypertensive therapy. Care patterns observed in the usual management of high blood pressure were not sufficient to achieve treatment goals or eliminate disparities.


Intracytoplasmic sperm injection outcome of ejaculated versus extracted testicular spermatozoa in cryptozoospermic men.
To compare intracytoplasmic sperm injection (ICSI) outcome of patients with cryptozoospermia after use of ejaculated versus testicular sperm in different cycles of the same patients. Retrospective cohort study. University-affiliated infertility center. A total of 17 patients with cryptozoospermia who underwent a total of 116 ICSI cycles. The patients initially underwent several ICSI cycles using ejaculated sperm (n = 68, 58.6%) that were followed by ICSI cycles using testicular sperm (n = 48, 41.4%). Fertilization rate, pregnancy rate (PR). There were no significant differences in fertilization rates between the two subgroups. A comparison between testicular sperm extraction (TESE) versus ejaculated sperm cycles revealed significantly higher implantation rate (20.7% vs. 5.7%), higher PR (42.5% vs. 15.1%), and higher take home baby rate (27.5% vs. 9.4%). A multivariable logistic regression analysis showed three significant predictors for pregnancy, namely the use of testicular sperm (odds ratio [OR] 5.1, 95% confidence interval [95% CI] 1.8-14.8), use of motile sperm (OR 12.9, 95% CI 2.1-79.1), and female age (OR 0.83, 95% CI 0.7-0.9). Testicular sperm extraction is justified in patients with cryptozoospermia who fail to conceive by ICSI using ejaculated spermatozoa, as it offers higher PR.


Detection of Legionella pneumophila in water samples by quantitative culture and an antigen detection assay.
We evaluated the new Legionella pneumophila antigen detection assay Binax Equate for quantitative determination of legionellae in potable water samples. Seventy-seven water samples from different sources were investigated by Binax Equate and quantitative culture. Our culture assay is able to detect 20 to 40 cfu per 100 ml water. The rates of detection of legionellae were 1% (1 of 77) for the antigen detection assay and 25% (19 of 77) by culture. We were able to detect antigen in one water sample with 28 cfu per ml L. pneumophila serogroup 1. In in-vitro experiments the antigen assay had a sensitivity of about 333 cfu per ml when the bacteria were added directly to the test tubes and about 1000 cfu per ml when a simulated water sample was investigated. None of the water samples positive for L. pneumophila serogroup 2 to 14 was positive in the Binax Equate. The new antigen assay proved to be a valuable tool for investigating heavy L. pneumophila Serogroup 1 contamination in potable water systems but lacks sufficient sensitivity to be used in the surveillance of water supplies.


Local effect of intranasal beclomethasone dipropionate aerosol in hay fever.
The effect of a daily dose of 400 mug beclomethasone dipropionate aerosol intranasally has been investigated in a double-blind cross-over trial in 29 patients with hay fever. The effect on the nasal symptoms was so pronounced in 25 patients that further symptomatic treatment was unnecessary. Beclomethasone dipropionate aerosol had, on the other hand, no direct effect on itching in the eyes, which is in accordance with the fact that biochemical investigations did not show any sign of suppression of the adrenal function. It is concluded that beclomethasone dipropionate aerosol intranasally is an effective and apparently harmless way of controlling the nasal symptoms in hay fever.


A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders.
Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating. Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans. Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis. Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender. DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline.


Structural evolution and mechanical behaviour of Pt nanoparticle superlattices at high pressure.
High pressure is an effective means for tuning the interparticle distances of nanoparticle (NP) superlattices and thus for modifying their physical properties and functionalities. In this work, we determined the evolution of inter-NP distances of a Pt NP superlattice with increasing pressure using an in situ synchrotron small-angle X-ray scattering (SAXS) technique in a diamond-anvil cell (DAC). Transmission electron microscopy (TEM) was used to characterize the microstructures of pre- and post-compression samples. Our results demonstrate that the evolution of Pt NP assemblies with increasing pressure consists of four stages: (1) ligand elastic response, (2) uniform compression, (3) ligand detachment from NP surfaces, and (4) deviatoric compression of ligands between neighboring NPs. By controlling the magnitudes of applied pressure and deviatoric stress, one can sinter NPs into novel architectures such as nanowires and nanoceramics.


Inconsistent association between the STK15 F31I genetic polymorphism and breast cancer risk.
STK15 may be a low-penetrance breast cancer susceptibility gene, and several reports suggest that women who are homozygous for the polymorphic variant F31I have an increased risk of breast cancer. To evaluate this potential breast cancer allele, we genotyped 507 patients with two primary breast cancers and 875 population-based control subjects for the STK15 F31I polymorphism. All statistical tests were two-sided. The Ile/Ile homozygous genotype was not associated with an increased risk in white women of British descent. The odds ratio for developing two primary breast cancers) in Ile/Ile homozygotes was 0.63 (95% confidence interval [CI] = 0.34 to 1.13), which corresponds to an odds ratio of 0.79 (95% CI = 0.58 to 1.06) for a first primary breast cancer. A meta-analysis of this study and other published studies showed statistically significant heterogeneity in the odds ratio estimates (P<.001). This heterogeneity could reflect either population-specific linkage disequilibrium with a functional variant or artifacts such as population stratification or publication bias.


The endosomal sorting complex ESCRT-II mediates the assembly and architecture of ESCRT-III helices.
The endosomal sorting complexes required for transport (ESCRTs) constitute hetero-oligomeric machines that mediate topologically similar membrane-sculpting processes, including cytokinesis, retroviral egress, and multivesicular body (MVB) biogenesis. Although ESCRT-III drives membrane remodeling that creates MVBs, its structure and the mechanism of vesicle formation are unclear. Using electron microscopy, we visualize an ESCRT-II:ESCRT-III supercomplex and propose how it mediates vesicle formation. We define conformational changes that activate ESCRT-III subunit Snf7 and show that it assembles into spiraling ~9 nm protofilaments on lipid monolayers. A high-content flow cytometry assay further demonstrates that mutations halting ESCRT-III assembly block ESCRT function. Strikingly, the addition of Vps24 and Vps2 transforms flat Snf7 spirals into membrane-sculpting helices. Finally, we show that ESCRT-II and ESCRT-III coassemble into ~65 nm diameter rings indicative of a cargo-sequestering supercomplex. We propose that ESCRT-III has distinct architectural stages that are modulated by ESCRT-II to mediate cargo capture and vesicle formation by ordered assembly.


Removal and relationships of microbial indicators in a water treatment and reclamation facility.
A wastewater treatment and reclamation facility in north-east Spain was monitored over 1 year to determine the occurrence and concentrations of different microbial indicators (Escherichia coli, fecal enterococci, somatic bacteriophages and spores of sulfite-reducing clostridia). The removal of the indicators and its relationships through the wastewater treatment and reclamation trains were evaluated. The results obtained show that the reclamation treatments evaluated present a different efficiency in indicator microorganisms' removal depending on the type of microorganism. The E. coli and enterococci present an average reduction slightly higher than the other indicators, followed by somatic bacteriophages and spores of sulfite-reducing clostridia. The Spearman's correlations indicate that it is not suitable to use any of the bacterial indicators evaluated to predict the content of virus or spores of sulfite-reducing clostridia. Therefore, in order to evaluate the microbiological risk of the reclaimed effluent use, it is necessary to monitor the three types of indicator microorganisms (bacteria, virus and protozoa).


Role of trastuzumab in the adjuvant treatment of HER2-positive early breast cancer.
Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18-23% of invasive breast carcinomas and is associated with a worse prognosis. This novel transforming gene was identified in 1985, and in 1987 HER2 amplification was demonstrated to be central to the aggressive, malignant phenotype of these cancers and a significant predictor of both time to relapse and overall survival. These observations led to the development of the first monoclonal antibody targeting the extracellular domain of HER2, trastuzumab (Herceptin, Genentech and Hoffman LaRoche, Switzerland), which was approved by the US FDA for metastatic breast cancer in 1998. In 2005, results from four major trastuzumab adjuvant trials demonstrated a marked reduction in risk of recurrence, and trastuzumab is now an essential component of the adjuvant treatment of HER2-positive early breast cancer. Concerns regarding cardiac safety and mechanisms of resistance to trastuzumab remain important issues and are being addressed in ongoing research efforts.


Pathology of 46,XY pure gonadal dysgenesis: absence of testis differentiation associated with mutations in the testis-determining factor.
Individuals with 46, XY pure gonadal dysgenesis present with a completely female phenotype. These individuals develop bilateral streak gonads and have normal Müllerian structures. The apparent absence of testicular tissue in these individuals suggests a mutation in the initial steps of the male sex-determining pathway. A candidate gene for the primary signal in this pathway was recently cloned (SRY) which encodes a protein with a DNA-binding capacity. In a study of 14 XY females with pure gonadal dysgenesis harbouring SRY, we analysed the histology of the gonads and compared it to the presence or absence of mutations in the SRY open reading frame (SRY-orf). The histological analysis revealed two distinct groups of streak gonads. In the first group, the gonad was composed of exclusively ovarian-like stroma, with sclero-hyaline nodules in some areas. No tubules were observed. The gonads in the second group were composed of undifferentiated stroma harbouring either tubules or a rete structure. This suggests that in the latter group some differentiation (towards testis formation) has occurred, whereas in the first group ovarian differentiation has been interrupted. Individuals with mutations in the SRY-orf were found to have streak gonads of the first group, whereas most of the remaining XY females without detectable mutation in the SRY-orf had streak gonads belonging to the second group. On the basis of histology, it may be possible to distinguish between mutations in the sex-determining or sex-differentiation pathways. We suggest that SRY may play a role in rete testis formation.(ABSTRACT TRUNCATED AT 250 WORDS)


Renal function and morphology in Sudanese patients with advanced hepatosplenic schistosomiasis and portal hypertension.
The association between glomerular disease and hepatosplenic schistosomiasis is well documented in reports from South America. During the present hospital investigation in Sudan, 58 patients admitted for intercurrent complications of advanced hepatosplenic schistosomiasis were studied. The patients, median age 35 years, had no concurrent Schistosoma haematobium infection. Diagnostic criteria included an enlarged spleen (n = 58), at least 1 episode of hematemesis (n = 55) and/or melena (n = 36), endoscopical demonstration of gastroesophageal varices (29/29 studied), ultrasonographical imaging of hepatic periportal fibrosis (18/18 studied), and intraoperative liver biopsy with characteristic histological findings (11/16 biopsied). Serum creatinine, urea, electrolytes, cholesterol, total protein, and electrophoresis were within normal limits. Median urinary protein/creatinine ratio was 0.06 and thereby not significantly different from European reference values. Only 1 patient had proteinuria of 1.7 g/l. Minimal hematuria was found in 5 patients. Ten kidney biopsies were taken intraoperatively during a portal decompression procedure (Hassab operation). Light, immunofluorescence, and electron microscopy produced no evidence of glomerulonephritis. These findings indicate that S. mansoni induced nephrotic syndrome may be less frequent in Sudan than in South America. Renal involvement due to S. mansoni infection may therefore encompass geographical variances.


Satisfaction with gastrostomy feeding in caregivers of children with home enteral nutrition; application of the SAGA-8 questionnaire and analysis of involved factors.
To assess the degree of satisfaction of caregivers of children with gastrostomy tube (GT) feeding through the structured questionnaire SAGA-8. Secondly, to evaluate if the parental satisfaction degree was related to several independent variables. A cross-sectional observational study was performed in 92 caregivers of children with GT feeding and chronic diseases. The following data was obtained: caregiver satisfaction with GT feeding (SAGA-8), age at GT placement, anthropometric data, length and mode of nutritional support, family demographic characteristics and caregiver psychological status. All primary caregivers were mothers. High satisfaction with GT feeding was expressed by 82.6% of families. The simplicity of the system was emphasized by 87%, and 85.9% were very satisfied with the support received from the hospital staff. 73.9% of mothers acknowledged their child's nutritional status had improved and 89.1% rated the enhancement family's overall situation. Moreover, 75% of mothers reduced feeding-time, and 68.5% reported less respiratory infections. Finally, 71.7% of mothers recognized that they would have implemented this technique earlier. Caregiver satisfaction was positively correlated with age at GT placement and length of treatment, and both variables explained the 19.4% of the satisfaction variance. No correlation with anthropometric data, nutrition support mode, family demographic characteristics or caregiver psychological status was observed. The SAGA-8 questionnaire is a simple, specific, straight-forward tool to evaluate parental/caregiver degree of satisfaction with GT feeding and facilitates effective monitoring of the intervention. Lengths of HEN and precocious age at GT placement are responsible for most of parental satisfaction.


Munc13 mediates klotho-inhibitable diacylglycerol-stimulated exocytotic insertion of pre-docked TRPC6 vesicles.
α-Klotho is a type 1 transmembrane protein that exhibits aging suppression function. The large amino-terminal extracellular domain of α-klotho is shed as soluble klotho (sKlotho) and functions as a circulating cardioprotective hormone. Diacylglycerol (DAG)-activated calcium-permeable TRPC6 channel plays a critical role in stress-induced cardiac remodeling. DAG activates TRPC6 by acting directly on the channel to increase its activity and by stimulation of channel exocytosis. sKlotho protects the heart by inhibiting DAG stimulation of TRPC6 exocytosis. How DAG stimulates TRPC6 exocytosis and thereby inhibition by sKlotho are unknown. Using a compound that directly activates TRPC6 without affecting channel exocytosis, we validate that sKlotho selectively blocks DAG stimulation of channel exocytosis. We further show that DAG stimulates exocytosis of TRPC6-containing vesicles pre-docked to the plasma membrane. Mnuc13 family proteins play important roles in the proper assembly of SNARE proteins and priming the vesicle competent for fusion. We show that DAG stimulates TRPC6 exocytosis by targeting to the C1 domain of Munc13-2. The results provide fresh insights into the molecular mechanism by which DAG regulates vesicle fusion and how sKlotho protects the heart against injury.


Human population growth and the demographic transition.
The world and most regions and countries are experiencing unprecedentedly rapid demographic change. The most obvious example of this change is the huge expansion of human numbers: four billion have been added since 1950. Projections for the next half century expect a highly divergent world, with stagnation or potential decline in parts of the developed world and continued rapid growth in the least developed regions. Other demographic processes are also undergoing extraordinary change: women's fertility has dropped rapidly and life expectancy has risen to new highs. Past trends in fertility and mortality have led to very young populations in high fertility countries in the developing world and to increasingly older populations in the developed world. Contemporary societies are now at very different stages of their demographic transitions. This paper summarizes key trends in population size, fertility and mortality, and age structures during these transitions. The focus is on the century from 1950 to 2050, which covers the period of most rapid global demographic transformation.


The out-of body experience: precipitating factors and neural correlates.
Out-of-body experiences (OBEs) are defined as experiences in which a person seems to be awake and sees his body and the world from a location outside his physical body. More precisely, they can be defined by the presence of the following three phenomenological characteristics: (i) disembodiment (location of the self outside one's body); (ii) the impression of seeing the world from an elevated and distanced visuo-spatial perspective (extracorporeal, but egocentric visuo-spatial perspective); and (iii) the impression of seeing one's own body (autoscopy) from this perspective. OBEs have fascinated mankind from time immemorial and are abundant in folklore, mythology, and spiritual experiences of most ancient and modern societies. Here, we review some of the classical precipitating factors of OBEs such as sleep, drug abuse, and general anesthesia as well as their neurobiology and compare them with recent findings on neurological and neurocognitive mechanisms of OBEs. The reviewed data suggest that OBEs are due to functional disintegration of lower-level multisensory processing and abnormal higher-level self-processing at the temporo-parietal junction. We argue that the experimental investigation of the interactions between these multisensory and cognitive mechanisms in OBEs and related illusions in combination with neuroimaging and behavioral techniques might further our understanding of the central mechanisms of corporal awareness and self-consciousness much as previous research about the neural bases of complex body part illusions such as phantom limbs has done.


Analysis of Entamoeba histolytica excretory-secretory antigen and identification of a new potential diagnostic marker.
Serodiagnosis of amoebiasis remains the preferred method for diagnosis of amoebic liver abscess (ALA). However, the commercially available kits are problematic in areas of endemicity due to the persistently high background antibody titers. Human serum samples (n = 38) from patients with ALA who live in areas of endemicity were collected from Hospital Universiti Sains Malaysia during the period of 2008 to 2010. Western blots using excretory-secretory antigen (ESA) collected from axenically grown Entamoeba histolytica were probed with the above serum samples. Seven antigenic proteins of ESA with various reactivities were identified, i.e., 152 kDa, 131 kDa, 123 kDa, 110 kDa, 100 kDa, 82 kDa, and 76 kDa. However, only the 152-kDa and 110-kDa proteins showed sensitivities above 80% in the Western blot analysis. All the antigenic proteins showed undetectable cross-reactivity when probed with healthy human serum samples (n = 30) and serum samples from other infections (n = 33). From the matrix-assisted laser desorption ionization-two-stage time of flight (MALDI-TOF/TOF) analysis, the proteins were identified as heavy subunits of E. histolytica lectin and E. histolytica pyruvate phosphate dikinase, respectively. Use of the E. histolytica lectin for diagnosis of ALA has been well reported by researchers and is being used in commercialized kits. However, this is the first report on the potential use of pyruvate phosphate dikinase for diagnosis of ALA; thus, this molecule merits further evaluation on its diagnostic value using a larger panel of serum samples.


[The structure of temperament sixth year students of the medical faculty of the medical university].
To assess differences in temperament traits in accordance with the regulatory theory of temperament J. Strelau in medical students compared to the general population matched for age and sex derived from the standardization sample of the questionnaire FCZ-KT. The study was conducted among 202 sixth year students of the Faculty of Medicine, Medical University of Łódź in the academic year 2008/2009. Among those respondents were 140 women (69%) and 62 men (31%). The average age of students enrolled was 24.7 years (range: 23-29). They were asked to complete a survey on demographic variables and temperament questionnaire FCZ-KT developed and standardized by B. Zawadzki and J. Strelau. There were no significant differences in the severity of the four temperament traits consistent with the theory of regulatory J. Strelau temperament: Lively, Sensory Sensitivity, Strength, and Activity. Significant differences were observed in the Perseverance (p < 0.0001) and Reactivity emotional (p < 0.0001), with a significantly lower severity of these characteristics were observed among the students of sixth year medical faculty in comparison with the general population. The strength of the effects observed, expressed as standardized difference in mean belongs to the moderate and significant (coefficient of Cohen's d > 0.6). Students of the Medical Faculty are substantially different from the temperamental traits of people in the same age range and same-sex couples in the general population. Students of the Medical Faculty are characterized by lower emotional reactivity and perseverance. Characterized by their weaker tendency to respond to intense emotions and the harmful stimuli associated with the greater resistance and less sensitivity and a weaker trend to continue their behavior and emotional experience after discontinuation of the situation which caused this behavior. Conduct a study of sixth year students of one medical school is likely to result in restrictions on the relevance of external applications and the ability to generalize the entire population of medical students in Poland.


Pharmacological modulation of dietary lipid-induced cerebral capillary dysfunction: Considerations for reducing risk for Alzheimer's disease.
An increasing body of evidence suggests that cerebrovascular dysfunction and microvessel disease precede the evolution of hallmark pathological features that characterise Alzheimer's disease (AD), consistent with a causal association for onset or progression. Recent studies, principally in genetically unmanipulated animal models, suggest that chronic ingestion of diets enriched in saturated fats and cholesterol may compromise blood-brain barrier (BBB) integrity resulting in inappropriate blood-to-brain extravasation of plasma proteins, including lipid macromolecules that may be enriched in amyloid-β (Aβ). Brain parenchymal retention of blood proteins and lipoprotein bound Aβ is associated with heightened neurovascular inflammation, altered redox homeostasis and nitric oxide (NO) metabolism. Therefore, it is a reasonable proposition that lipid-lowering agents may positively modulate BBB integrity and by extension attenuate risk or progression of AD. In addition to their robust lipid lowering properties, reported beneficial effects of lipid-lowering agents were attributed to their pleiotropic properties via modulation of inflammation, oxidative stress, NO and Aβ metabolism. The review is a contemporary consideration of a complex body of literature intended to synthesise focussed consideration of mechanisms central to regulation of BBB function and integrity. Emphasis is given to dietary fat driven significant epidemiological evidence consistent with heightened risk amongst populations consuming greater amounts of saturated fats and cholesterol. In addition, potential neurovascular benefits associated with the use of hypolipidemic statins, probucol and fenofibrate are also presented in the context of lipid-lowering and pleiotropic properties.


Fast and Accurate Estimation of Species-Specific Diversification Rates Using Data Augmentation.
Diversification rates vary across species as a response to various factors, including environmental conditions and species-specific features. Phylogenetic models that allow accounting for and quantifying this heterogeneity in diversification rates have proven particularly useful for understanding clades diversification. Recently, we introduced the cladogenetic diversification rate shift model, which allows inferring multiple rate changes of small magnitude across lineages. Here, we present a new inference technique for this model that considerably reduces computation time through the use of data augmentation and provide an implementation of this method in Julia. In addition to drastically reducing computation time, this new inference approach provides a posterior distribution of the augmented data, that is the tree with extinct and unsampled lineages as well as associated diversification rates. In particular, this allows extracting the distribution through time of both the mean rate and the number of lineages. We assess the statistical performances of our approach using simulations and illustrate its application on the entire bird radiation.[Birth-death model; data augmentation; diversification; macroevolution.].


Drug Policy and the Public Good: a summary of the book.
Drug Policy and the Public Good was written by an international group of scientists from the fields of addiction, public health, criminology and policy studies to improve the linkages between drug research and drug policy. The book provides a conceptual basis for evidence-informed drug policy and describes epidemiological data on the global dimensions of drug misuse. The core of the book is a critical review of the cumulative scientific evidence in five general areas of drug policy: primary prevention programmes in schools and other settings; health and social services for drug users; attempts to control the supply of drugs, including the international treaty system; law enforcement and ventures into decriminalization; and control of the psychotropic substance market through prescription drug regimes. The final chapters discuss the current state of drug policies in different parts of the world and describe the need for future approaches to drug policy that are coordinated and informed by evidence.


Cytogenetic comparison of saola (Pseudoryx nghetinhensis) and cattle (Bos taurus) using G- and Q-banding and FISH.
In order to cytogenetically describe the new bovid species saola (Pseudoryx nghetinhensis), comparative G- and Q-banding of saola and cattle (Bos taurus) chromosomes as well as FISH-mapping of 32 type-I markers (29 Texas markers and three additional markers) on saola chromosomes were performed. Saola was shown to have a diploid number of 2n = 50 chromosomes possessing five biarmed autosomal pairs and an acrocentric X chromosome. Homology of saola and cattle chromosomes was indicated by banding patterns and by marker hybridization suggesting that all five biarmed pairs in saola originate from centric fusions involving ten cattle autosomes. However, small intrachromosomal rearrangements cannot be excluded. In this study the first preliminary homology map of these two species is presented.


Sexual health and quality of life among male veterans with intestinal ostomies.
This secondary analysis was conducted to expand our understanding of the challenges men with ostomies face regarding intimate relationships and sexual functioning. We examined quantitative and qualitative data to examine sexual functioning, intimate relationships, and health-related quality of life (HR-QOL) among military veterans who are living with an intestinal stoma. Three Veterans Health Administration sites. Four hundred eighty-one male veterans. Case-control, mixed-methods design; cases were those who had ostomies for at least 2 months, and controls had a similar major intestinal surgical procedure that did not result in an ostomy. Quantitative and qualitative data on sexual functioning, relationships, and other dimensions of HR-QOL were collected using the modified City of Hope Quality of Life-Ostomy questionnaire. The overall response rate was 49%. Prevalence of erectile dysfunction was significantly higher among ostomates compared with controls (P < .001). Although a greater proportion of veterans with ostomies reported being sexually active before surgery compared with controls (P < .001), the proportion of men who had resumed sexual activity after surgery is significantly lower among the ostomy group (P = .015). Compared with veterans with ostomies who did not resume sexual activity after surgery, those who were sexually active reported a higher total HR-QOL score and higher scores on all 4 modified City of Hope Quality of Life-Ostomy dimensions (psychological, social, physical, and spiritual well-being). Veterans with ostomies who had resumed sexual activity after their ostomy also reported that their ostomy had caused significantly less interference with social activities, less isolation, less interference with their personal relationships, and less interference with their ability to be intimate. These men also reported less difficulty adjusting to the ostomy. Results of qualitative analyses showed that problems with intimacy and sexual function are among the greatest challenges faced by ostomates. Presence of an ostomy was associated with lower rates of sexual activity and higher erectile dysfunction. The lower rates of sexual activity and sexual satisfaction were related to the social and psychological dimensions of HR-QOL among men with ostomies. Interventions to address sexual concerns of male ostomates and their partners may prevent decrements to HR-QOL for these patients. Results of the study have implications for the clinical nurse specialist role in supporting and educating patients with ostomies to minimize the negative impact of an intestinal ostomy on sexual health and HR-QOL. Implications also relate to the need to educate current and future nurses about the importance of assessing sexual health.


Truncated estrogen receptor alpha 46-kDa isoform in human endothelial cells: relationship to acute activation of nitric oxide synthase.
Estrogen acutely activates endothelial nitric oxide synthase (eNOS). However, the identity of the receptors involved in this rapid response remains unclear. We detected an estrogen receptor alpha (ERalpha) transcript in human endothelial cells that encodes a truncated 46-kDa ERalpha (Delta1a-hERalpha-46). A corresponding 46-kDa ERalpha protein was identified in endothelial cell lysates. Transfection of cDNAs encoding the full-length ERalpha (ERalpha-66) and Delta1a-hERalpha-46 resulted in appropriately sized recombinant proteins identified by anti-ERalpha antibodies. Confocal microscopy revealed that a proportion of both ERalpha-66 and hERalpha-46 was localized outside the nucleus and mediated specific cell-surface binding of estrogen as assessed by FITC-conjugated, BSA-estrogen binding studies. Both ERalpha isoforms colocalized with eNOS and mediated acute activation of eNOS in response to estrogen stimulation. However, estrogen-stimulated transcriptional activation mediated by Delta1a-hERalpha-46 was much less than with ERalpha-66. Furthermore, Delta1a-hERalpha-46 inhibited classical hERalpha-66-mediated transcriptional activation in a dominant-negative fashion. These findings suggest that expression of an alternatively spliced, truncated ERalpha isoform in human endothelial cells confers a unique ability to mediate acute but not transcriptional responses to estrogen.


Recent progress in allergen immunotherapy.
The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by peripheral T cells. Recent researches into the cellular and molecular basis of allergic reactions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to further improve the control of allergic responses in the future. Novel approaches to immunotherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both Th1 and Th2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory sequences derived from bacteria CpG or monophosphoryl lipid A that potentiate Th1 responses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the development of TReg cells producing cytokines such as IL-10.


The Regulation of Mitochondrial Replacement Techniques Around the World.
Mitochondrial replacement techniques (MRTs, also referred to as mitochondrial replacement therapies) have given hope to many women who wish to have genetically related children but have mitochondrial DNA mutations in their eggs. MRTs have also spurred deep ethical disagreements and led to different regulatory approaches worldwide. In this review, we discuss the current regulation of MRTs across several countries. After discussing the basics of the science, we describe the current law and policy directions in seven countries: the United Kingdom, the United States, Canada, Australia, Germany, Israel, and Singapore. We also discuss the emerging phenomenon of medical tourism (also called medical travel) for MRTs to places like Greece, Spain, Mexico, and Ukraine. We then pull out some key findings regarding similarities and differences in regulatory approaches around the world.


Mechanisms of IVIG efficacy in chronic inflammatory demyelinating polyneuropathy.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy. Corticosteroids, plasmapheresis and intravenous immunoglobulins (IVIG) have been shown to be effective in randomized controlled clinical trials and IVIG is widely used as a first-line initial and maintenance treatment for CIDP. Studies in animal models of autoimmune diseases indicated that the inhibitory Fc-gamma receptor FcgammaRIIB, expressed on myeloid cells and B cells, is required for the anti-inflammatory activity of IVIG. We found that untreated patients with CIDP, compared to demographically matched healthy controls, show lower FcgammaRIIB expression levels on naïve B cells and fail to upregulate or to maintain upregulation of FcgammaRIIB as B cells progress from the naive to the memory compartment. Furthermore, FcgammaRIIB protein expression is upregulated on B cells and monocytes following clinically effective IVIG therapy suggesting that impaired expression of the inhibitory FcgammaR in CIDP can, at least partially, be restored by IVIG treatment. In B cells, FcgammaRIIB transduces an inhibitory signal upon colligation with the B cell receptor, thereby preventing B cells with low affinity or self-reactive receptors from entering the germinal center and becoming IgG positive plasma cells. Our data suggest that this late B cell differentiation checkpoint is impaired in CIDP. Modulating FcgammaRIIB function might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.


Effects of poly(ethylene glycol) on the wetting behavior and director configuration of lyotropic chromonic liquid crystals confined in cylinders.
We investigate the effects of poly(ethylene glycol) (PEG) doping on nematic lyotropic chromonic liquid crystals (LCLCs) confined in a cylindrical cavity. First, PEG added to Sunset Yellow (SSY) renders confining glass surfaces nemato-phobic by adsorption. We also confirm that the grafting of PEG to bare glass surfaces changes them from nemato-philic to nemato-phobic. This change in the wetting behavior affects how nematic director configurations form and relax. Additionally, we observe that PEG-doped nematic SSY retains the double-twist director configuration as in the PEG-free case. However, the PEG-doped nematic SSY is accompanied by unprecedented domain-wall-like defects and heterogeneity in the director configuration. We propose multiple hypotheses on how PEG changes the director configuration, including the formation of meta-stable director configurations.


Activity-independent cell adhesion to tissue-type transglutaminase is mediated by alpha4beta1 integrin.
Transglutaminases (TGases) are enzymes which catalyze cross-link formation between glutamine residues and lysine residues in substrate proteins. We have previously reported that one of the TGases, blood coagulation factor XIIIa (FXIIIa), is capable of mediating adhesion of various cells. In this paper, we report for the first time that tissue-type transglutaminase (TGc) also has cell adhesion activity. TGc-coated plastic surface promoted adhesion and spreading of cells in a TGc concentration-dependent manner. However, there are some obvious differences between cell adhesion mediated by TGc and FXIIIa. As was reported previously, the adhesion to FXIIIa is dependent on its TGase activity. In contrast, the TGc-mediated cell adhesion is independent of its TGase activity: 1) The modification of the active center cysteine with iodoacetamide blocked the enzyme activity without any effect on cell adhesion; 2) the addition of Mg2+ did not induce the enzyme activity, but it was as effective as Ca2+ for cell adhesion; 3) the addition of NH4+ inhibited the enzyme activity but did not affect the cell adhesion significantly. The integrins involved in these cell adhesions are quite different. In the case of FXIIIa, alpha vbeta3 and alpha5beta1 integrins are involved and consequently the RGD peptide substantially inhibited the adhesion. On the other hand, the cell adhesion to TGc is mediated by alpha4beta1 integrin but not alpha5beta1; a CS-1 peptide, which represents the binding site of fibronectin to alpha4beta1 integrin, completely inhibited the cell adhesion to TGc. It is possible that TGc and FXIIIa may mediate cell adhesion under different physiological and pathological situations.


Automated Virtual Reality Cognitive Therapy (gameChange) in Inpatient Psychiatric Wards: Qualitative Study of Staff and Patient Views Using an Implementation Framework.
Automated virtual reality (VR) therapy could allow a greater number of patients to receive evidence-based psychological therapy. The aim of the gameChange VR therapy is to help patients overcome anxious avoidance of everyday social situations. gameChange has been evaluated with outpatients, but it may also help inpatients prepare for discharge from psychiatric hospital. The aim of this study is to explore the views of patients and staff on the provision of VR therapy on psychiatric wards. Focus groups or individual interviews were conducted with patients (n=19) and National Health Service staff (n=22) in acute psychiatric wards. Questions were derived from the nonadoption, abandonment, and challenges to the scale-up, spread, and sustainability framework. Expectations of VR therapy were discussed, and participants were then given the opportunity to try out the gameChange VR therapy before they were asked questions that focused on opinions about the therapy and feasibility of adoption. There was great enthusiasm for the use of gameChange VR therapy on psychiatric wards. It was considered that gameChange could help build confidence, reduce anxiety, and "bridge that gap" between the differences of being in hospital and being discharged to the community. However, it was reflected that the VR therapy may not suit everyone, especially if they are acutely unwell. VR on hospital wards for entertainment and relaxation was also viewed positively. Participants were particularly impressed by the immersive quality of gameChange and the virtual coach. It was considered that a range of staff groups could support VR therapy delivery. The staff thought that implementation would be facilitated by having a lead staff member, having ongoing training accessible, and involving the multidisciplinary team in decision-making for VR therapy use. The most significant barrier to implementation identified by patients and staff was a practical one: access to sufficient, private space to provide the therapy. Patients and staff were keen for VR to be used on psychiatric wards. In general, patients and staff viewed automated VR therapy as possible to implement within current care provision, with few significant barriers other than constraints of space. Patients and staff thought of many further uses of VR on psychiatric wards. The value of VR therapy on psychiatric wards now requires systematic evaluation. RR2-10.2196/20300.


Intraspecific facilitation by allelochemical mediated grazing protection within a toxigenic dinoflagellate population.
Dinoflagellates are a major cause of harmful algal blooms (HABs), with consequences for coastal marine ecosystem functioning and services. Alexandrium fundyense (previously Alexandrium tamarense) is one of the most abundant and widespread toxigenic species in the temperate Northern and Southern Hemisphere and produces paralytic shellfish poisoning toxins as well as lytic allelochemical substances. These bioactive compounds may support the success of A. fundyense and its ability to form blooms. Here we investigate the impact of grazing on monoclonal and mixed set-ups of highly (Alex2) and moderately (Alex4) allelochemically active A. fundyense strains and a non-allelochemically active conspecific (Alex5) by the heterotrophic dinoflagellate Polykrikos kofoidii. While Alex4 and particularly Alex5 were strongly grazed by P. kofoidii when offered alone, both strains grew well in the mixed assemblages (Alex4 + Alex5 and Alex2 + Alex5). Hence, the allelochemical active strains facilitated growth of the non-active strain by protecting the population as a whole against grazing. Based on our results, we argue that facilitation among clonal lineages within a species may partly explain the high genotypic and phenotypic diversity of Alexandrium populations. Populations of Alexandrium may comprise multiple cooperative traits that act in concert with intraspecific facilitation, and hence promote the success of this notorious HAB species.


Synovial sarcoma of the maxillary sinus: an extremely rare case with excellent response to chemotherapy.
This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ~10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treatment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was successfully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of "complete response". The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case.


Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.
Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT-D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT-D patients with heart failure. In a multicentre, randomised study, patients with chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%) have been identified and screened. One hundred and ninety-one patients have been randomised to receive either a CRT-D with TM or a CRT-D with traditional ambulatory monitoring (control group) and completed the 12-month study follow-up. Primary endpoints were all cause death, cardiac death and hospital admission for heart failure. Secondary endpoints were atrial fibrillation, sustained episodes, non-sustained and self terminated ventricular tachyarrhythmia, sustained ventricular tachycardia, and ventricular fibrillation, ICD shocks and percentage of CRT-D responder patients. Univariate analysis identified the following factors predicting hospitalisation: TM, age, chronic kidney disease, hypercholesterolaemia, LVEF and NYHA class. At multivariate analysis, TM was the only factor predicting heart failure hospitalisation (hazard ratio 0.6, 0.42-0.79, 95% CI, p = 0.002), without affecting overall mortality and cardiac deaths events. Taken together, our data indicate the importance of TM in predicting heart failure hospitalisation in patients treated with CRT-D.


Selective Aptamers for Detection of Estradiol and Ethynylestradiol in Natural Waters.
We used in vitro selection to identify new DNA aptamers for two endocrine-disrupting compounds often found in treated and natural waters, 17β-estradiol (E2) and 17α-ethynylestradiol (EE). We used equilibrium filtration to determine aptamer sensitivity/selectivity and dimethyl sulfate (DMS) probing to explore aptamer binding sites. The new E2 aptamers are at least 74-fold more sensitive for E2 than is a previously reported DNA aptamer, with dissociation constants (Kd values) of 0.6 μM. Similarly, the EE aptamers are highly sensitive for EE, with Kd of 0.5-1.0 μM. Selectivity values indicate that the E2 aptamers bind E2 and a structural analogue, estrone (E1), equally well and are up to 74-fold selective over EE. One EE aptamer is 53-fold more selective for EE over E2 or E1, but the other binds EE, E2, and E1 with similar affinity. The new aptamers do not lose sensitivity or selectivity in natural water from a local lake, despite the presence of natural organic matter (∼4 mg/L TOC). DMS probing suggests that E2 binding occurs in relatively flexible single-stranded DNA regions, an important finding for rational redesign of aptamers and their incorporation into sensing platforms. This is the first report of aptamers with strong selectivity for E2 and E1 over EE, or with strong selectivity for EE over E2 and E1. Such selectivity is important for achieving the goal of creating practically useful DNA-based sensors that can distinguish structurally similar estrogenic compounds in natural waters.


Pyrexia after transcranial surgery for Pfeiffer syndrome.
Previously, we have reported the pattern of temperature increase after transcranial surgery for nonsyndromic craniosynostosis. It was found that pyrexia had a bimodal distribution during the first 48 hours after surgery. The aims of this study were to evaluate pyrexia after transcranial surgery for syndromic craniosynostosis (Pfeiffer syndrome), to investigate whether the same pattern occurred, and to evaluate the correlation between pyrexia and possible factors, that is, sex, age, procedure, length of surgery, and incidence of postoperative cerebrospinal fluid (CSF) leakage. Twenty-one sequential case notes of Pfeiffer syndrome were retrospectively reviewed to collect 38 postoperative temperature courses. The mean change of temperature was plotted on a graph with a trend line to find the feature of the course. Pyrexia after transcranial surgery for Pfeiffer syndrome had a bimodal distribution during the first 48 hours, similar to the pyrexia after transcranial surgery for nonsyndromic craniosynostosis. This pyrexia was higher and more prolonged in those undergoing a longer surgical procedure and frontofacial advancement and procedures accompanied with postoperative CSF leakage. Moreover, the temperature course was more complex in procedures accompanied with postoperative CSF leakage. It was concluded that in Pfeiffer syndrome, which has more complicated pathologic status than nonsyndromic craniosynostosis, also had bimodal postoperative temperature course. Although the etiology of the bimodal pyrexia remains unclear, it seems that it is part of the normal postoperative course in these cases. However, prolonged raised temperature within the first 48 postoperative hours may suggest a complication.


Factors Affecting Targeted Sequencing of 353 Nuclear Genes From Herbarium Specimens Spanning the Diversity of Angiosperms.
The world's herbaria collectively house millions of diverse plant specimens, including endangered or extinct species and type specimens. Unlocking genetic data from the typically highly degraded DNA obtained from herbarium specimens was difficult until the arrival of high-throughput sequencing approaches, which can be applied to low quantities of severely fragmented DNA. Target enrichment involves using short molecular probes that hybridise and capture genomic regions of interest for high-throughput sequencing. In this study on herbariomics, we used this targeted sequencing approach and the Angiosperms353 universal probe set to recover up to 351 nuclear genes from 435 herbarium specimens that are up to 204 years old and span the breadth of angiosperm diversity. We show that on average 207 genes were successfully retrieved from herbarium specimens, although the mean number of genes retrieved and target enrichment efficiency is significantly higher for silica gel-dried specimens. Forty-seven target nuclear genes were recovered from a herbarium specimen of the critically endangered St Helena boxwood, Mellissia begoniifolia, collected in 1815. Herbarium specimens yield significantly less high-molecular-weight DNA than silica gel-dried specimens, and genomic DNA quality declines with sample age, which is negatively correlated with target enrichment efficiency. Climate, taxon-specific traits, and collection strategies additionally impact target sequence recovery. We also detected taxonomic bias in targeted sequencing outcomes for the 10 most numerous angiosperm families that were investigated in depth. We recommend that (1) for species distributed in wet tropical climates, silica gel-dried specimens should be used preferentially; (2) for species distributed in seasonally dry tropical climates, herbarium and silica gel-dried specimens yield similar results, and either collection can be used; (3) taxon-specific traits should be explored and established for effective optimisation of taxon-specific studies using herbarium specimens; (4) all herbarium sheets should, in future, be annotated with details of the preservation method used; (5) long-term storage of herbarium specimens should be in stable, low-humidity, and low-temperature environments; and (6) targeted sequencing with universal probes, such as Angiosperms353, should be investigated closely as a new approach for DNA barcoding that will ensure better exploitation of herbarium specimens than traditional Sanger sequencing approaches.


The missing linker: a dimerization motif located within polyketide synthase modules.
The dimerization of multimodular polyketide synthases is essential for their function. Motifs that supplement the contacts made by dimeric polyketide synthase enzymes have previously been characterized outside the boundaries of modules, at the N- and C-terminal ends of polyketide synthase subunits. Here we describe a heretofore uncharacterized dimerization motif located within modules. The dimeric state of this dimerization element was elucidated through the 2.6 Å resolution crystal structure of a fragment containing a dimerization element and a ketoreductase. The solution structure of a standalone dimerization element was revealed by nuclear magnetic resonance spectroscopy to be consistent with that of the crystal structure, and its dimerization constant was measured through analytical ultracentrifugation to be ∼20 μM. The dimer buries ∼990 Å(2) at its interface, and its C-terminal helices rigidly connect to ketoreductase domains to constrain their locations within a module. These structural restraints permitted the construction of a common type of polyketide synthase module.


Intrinsic bursters increase the robustness of rhythm generation in an excitatory network.
The pre-Botzinger complex (pBC) is a vital subcircuit of the respiratory central pattern generator. Although the existence of neurons with pacemaker-like bursting properties in this network is not questioned, their role in network rhythmogenesis is unresolved. Modeling is ideally suited to address this debate because of the ease with which biophysical parameters of individual cells and network architecture can be manipulated. We modeled the parameter variability of experimental data from pBC bursting pacemaker and nonpacemaker neurons using a modified version of our previously developed pBC neuron and network models. To investigate the role of pacemakers in networkwide rhythmogenesis, we simulated networks of these neurons and varied the fraction of the population made up of pacemakers. For each number of pacemaker neurons, we varied the amount of tonic drive to the network and measured the frequency of synchronous networkwide bursting produced. Both excitatory networks with all-to-all coupling and sparsely connected networks were explored for several levels of synaptic coupling strength. Networks containing only nonpacemakers were able to produce networkwide bursting, but with a low probability of bursting and low input and output ranges. Our results indicate that inclusion of pacemakers in an excitatory network increases robustness of the network by more than tripling the input and output ranges compared with networks containing no pacemakers. The largest increase in dynamic range occurs when the number of pacemakers in the network is greater than 20% of the population. Experimental tests of our model predictions are proposed.


Effects of allocare-givers on fitness of infants and parents in callitrichid primates.
The effects of callitrichid primate helpers (allocare-givers other than an infant's father) on the survival, reproduction or behavior of infants and parents are reviewed, using both published studies and data from free-ranging golden lion tamarins (Leontopithecus rosalia). Three lines of evidence suggest that helpers may increase their own inclusive fitness: (1) The number of adult males acting as helpers in free-ranging groups is correlated with the number of surviving infants in 3 callitrichid species. However, the lack of a negative correlation with number of infants dying suggests that activities other than direct infant care (e.g. territory defense) may be more important, especially in newly formed groups. (2) In 2 species, captive groups with helpers carry infants for longer periods of time than do groups without helpers. Whether such differences would translate into meaningful survival differences in free-ranging groups is unclear. (3) Helpers reduce the energetic burden of parents by reducing the amount of time they spend transporting or provisioning infants in at least 4 species. Reproductive males are more likely than reproductive females to benefit from the presence of helpers, reducing their investment in infant care activities as the number of helpers in the group increases. In free-ranging golden lion tamarins, the reproductive tenure of males, but not females, increases with the number of helpers in the group, suggesting that a reduction in energetic investment may translate into increased survival. 'Decisions' made by helpers to participate in infant transport are weighed against competing needs for foraging, vigilance, territory defense and, in some cases, prospecting for breeding opportunities. Given this complexity, a sophisticated model may be required to answer the question of how helpers 'decide' to participate in infant care versus other activities.


Likelihood of Return to Duty Is Low After Meniscal Allograft Transplantation in an Active-duty Military Population.
Meniscal allograft transplantation (MAT) is considered a viable surgical treatment option in the symptomatic, postmeniscectomy knee and as a concomitant procedure with ACL revision and articular cartilage repair. Although promising outcomes have recently been reported in active and athletic populations, MAT has not been well-studied in the high-demand military population. (1) What proportion of active-duty military patients who underwent MAT returned to full, unrestricted duty? (2) What demographic and surgical variables, if any, correlated with return to full, unrestricted duty? Between 2005 and 2015, three fellowship-trained sports surgeons (TMD, SJS, BDO) performed 110 MAT procedures in active-duty military patients, of which 95% (104 patients) were available for follow-up at a minimum 2 years (mean 2.8 ± SD 1.1 year). During the study period, indications for MAT generally included unicompartmental pain and swelling in a postmeniscectomized knee and as a concomitant procedure when a meniscal-deficient compartment was associated with either an ACL revision reconstruction or cartilage repair. Demographic and surgical variables were collected and analyzed. The primary endpoints were the decision for permanent profile activity restrictions and military duty termination by a medical board. The term "medical board" implies termination of military service because of medical reasons. We elected to set statistical significance at p < 0.001 to reduce the potential for spurious statistical findings in the setting of a relatively small sample size. Forty-six percent (48 of 104) of eligible patients had permanent profile activity restrictions and 50% (52 of 104) eventually had their military duty terminated by a military board. Only 20% (21 of 104) had neither permanent profile activity restrictions nor medical-board termination and were subsequently able to return to full duty, and only 13% (13 of 104) continued unrestricted military service beyond 2 years after surgery. Age, gender, tobacco use, and BMI did not correlate with return to full duty. Combat arms soldiers were less likely to have permanent profile activity restrictions (odds ratio 4.76 [95% confidence interval 1.93 to 11.8]; p = 0.001) and were more likely to return to full duty than soldiers in support roles (OR 0.24 [95% CI 0.09 to 0.65]; p = 0.005), although these findings did not reach statistical significance. Officers were more likely to return to full duty than enlisted soldiers at more than 2 years after surgery (OR 17.44 [95% CI 4.56 to 66.65]; p < 0.001). No surgical variables correlated with return-to-duty endpoints. Surgeons should be aware of the low likelihood of return to military duty at more than 2 years after MAT and counsel patients accordingly. Based on this study, MAT does not appear to be compatible with continued unrestricted military duty for most patients. IV, therapeutic study.


Characterization of Naturally Acquired Immunity to a Panel of Antigens Expressed in Mature P. falciparum Gametocytes.
Naturally acquired immune responses against antigens expressed on the surface of mature gametocytes develop in individuals living in malaria-endemic areas. Evidence suggests that such anti-gametocyte immunity can block the development of the parasite in the mosquito, thus playing a role in interrupting transmission. A better comprehension of naturally acquired immunity to these gametocyte antigens can aid the development of transmission-blocking vaccines and improve our understanding of the human infectious reservoir. Antigens expressed on the surface of mature gametocytes that had not previously been widely studied for evidence of naturally acquired immunity were identified for protein expression alongside Pfs230-C using either the mammalian HEK293E or the wheat germ cell-free expression systems. Where there was sequence variation in the candidate antigens (3D7 vs a clinical isolate PfKE04), both variants were expressed. ELISA was used to assess antibody responses against these antigens, as well as against crude stage V gametocyte extract (GE) and AMA1 using archived plasma samples from individuals recruited to participate in malaria cohort studies. We analyzed antibody levels (estimated from optical density units using a standardized ELISA) and seroprevalence (defined as antibody levels greater than three standard deviations above the mean levels of a pool of malaria naïve sera). We described the dynamics of antibody responses to these antigens by identifying factors predictive of antibody levels using linear regression models. Of the 25 antigens selected, seven antigens were produced successfully as recombinant proteins, with one variant antigen, giving a total of eight proteins for evaluation. Antibodies to the candidate antigens were detectable in the study population (N = 216), with seroprevalence ranging from 37.0% (95% CI: 30.6%, 43.9%) for PSOP1 to 77.8% (95% CI: 71.6%, 83.1%) for G377 (3D7 variant). Responses to AMA1 and GE were more prevalent than those to the gametocyte proteins at 87.9% (95% CI: 82.8%, 91.9%) and 88.3% (95% CI: 83.1%, 92.4%), respectively. Additionally, both antibody levels and breadth of antibody responses were associated with age and concurrent parasitaemia. Age and concurrent parasitaemia remain important determinants of naturally acquired immunity to gametocyte antigens. Furthermore, we identify novel candidates for transmission-blocking activity evaluation.


Resveratrol in lung cancer- a systematic review.
Resveratrol, a phytochemical known for its anti- oxidative properties has been explored worldwide for anticancer potential. We performed this systematic review and meta-analysis in order to register the efficacy of resveratrol against lung carcinogenesis. We searched PubMed for preclinical studies reporting efficacy of resveratrol alone or in combination with drugs like curcumin, cisplatin etc. against lung carcinogenesis. The primary outcome of eligible studies included change in overall tumor incidence as well as tumor size. In all of the above studies involving either animal models or in vitro cancer cell experiments a statistically significant reduction in tumor incidence emerged as compared with the control groups, yielding a relative risk reduction of 0.64 (p=0.002). This meta- analysis confirmed the potential of resveratrol against lung carcinogenesis. It can be concluded that resveratrol holds a good potential for future use as a highly efficient therapeutic agent to deal with deadly lung carcinogenesis.


Identification of sokotrasterol sulfate as a novel proangiogenic steroid.
The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2beta,3alpha,6alpha-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of alpha(v)beta(3) integrin was also necessary for function, as neutralization of alpha(v)beta(3) integrin, but not beta(1) integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.


Absorption-sensitive diffuse reflection imaging of concealed powders using a terahertz quantum cascade laser.
We report diffuse reflection imaging in air of concealed powdered samples using a terahertz quantum cascade laser. The sensitivity of the detection scheme to sub-surface absorption within samples is confirmed using fully-characterized powdered admixtures of polystyrene and polymethyl methacrylate (PMMA). Measurements of the backscattering intensity from these samples are then used in conjunction with Kubelka-Munk scattering theory, as well as several models based on the quasi-crystalline approximation, to extract the absorption coefficient of PMMA. Our research demonstrates the feasibility of high-resolution frequency-domain terahertz imaging for the detection and identification of concealed powders in a reflection geometry.


Junctional diversity in signal joints from T cell receptor beta and delta loci via terminal deoxynucleotidyl transferase and exonucleolytic activity.
The site-specific V(D)J recombination reaction necessary to assemble the genes coding for immunoglobulin (Ig) and T cell receptor (TCR) variable regions is initiated by a precise double strand cut at the border of the recombination signals flanking the genes. Extensive processing of the coding ends before their ligation accounts for most of the Ig and TCR repertoire diversity. This processing includes both base additions to and loss from the coding ends. On the other hand, it has generally been thought that signal ends are not modified before they are fused, and that signal joints consist of a perfect head-to-head ligation of the recombination signals. In this study, we analyzed signal joints created during the rearrangement of different TCR-beta and TCR-delta genes in thymocytes. We show that a significant fraction (up to 24%) of these signal joints exhibits junctional diversity. This diversity results from N nucleotide additions for TCR-beta signal joints, and from N additions and exonucleolytic digestion for TCR-delta joints. Altogether, our findings suggest that: (a) signal ends can undergo some of the same modifications as coding ends, (b) inversional rearrangement generates more diversity than deletional events, and (c) fine differences exist in the recombinase/DNA complexes formed at each rearranging locus.


Prevalence of HIV in a largely indigent obstetric population of Tarrant County, Texas.
To establish the seroprevalence of the human immunodeficiency virus (HIV) in our county hospital obstetric patients, and to assess the predictive value of screening questionnaires for high-risk behaviors attributing to HIV infection, we conducted written surveys and blinded HIV testing over a 4-month period ending February 1993. Blinded HIV antibody testing was performed on 1348 patients upon admission to labor and delivery. The coded blood samples were matched to similarly coded surveys of patient demographics and behaviors implicated in HIV transmission. The overall HIV prevalence in our regional population remains virtually unchanged at a rate of 0.22% (2.2 per 1000 patients). Questionnaires regarding health history were not predictive for HIV infection in our patients. Universal screening questionnaires cannot predict HIV infection. Similarly, routine mandatory testing for HIV performed on obstetric patients on the day of delivery are not cost-effective and do not provide clinically meaningful information needed to alter management protocols.


Reduced B12 uptake and increased gastrointestinal formate are associated with archaeome-mediated breath methane emission in humans.
Methane is an end product of microbial fermentation in the human gastrointestinal tract. This gas is solely produced by an archaeal subpopulation of the human microbiome. Increased methane production has been associated with abdominal pain, bloating, constipation, IBD, CRC or other conditions. Twenty percent of the (healthy) Western populations innately exhale substantially higher amounts (>5 ppm) of this gas. The underlying principle for differential methane emission and its effect on human health is not sufficiently understood. We assessed the breath methane content, the gastrointestinal microbiome, its function and metabolome, and dietary intake of one-hundred healthy young adults (female: n = 52, male: n = 48; mean age =24.1). On the basis of the amount of methane emitted, participants were grouped into high methane emitters (CH4 breath content 5-75 ppm) and low emitters (CH4 < 5 ppm). The microbiomes of high methane emitters were characterized by a 1000-fold increase in Methanobrevibacter smithii. This archaeon co-occurred with a bacterial community specialized on dietary fibre degradation, which included members of Ruminococcaceae and Christensenellaceae. As confirmed by metagenomics and metabolomics, the biology of high methane producers was further characterized by increased formate and acetate levels in the gut. These metabolites were strongly correlated with dietary habits, such as vitamin, fat and fibre intake, and microbiome function, altogether driving archaeal methanogenesis. This study enlightens the complex, multi-level interplay of host diet, genetics and microbiome composition/function leading to two fundamentally different gastrointestinal phenotypes and identifies novel points of therapeutic action in methane-associated disorders. Video Abstract.


Asthma in sickle cell disease: implications for treatment.
Objective. To review issues related to asthma in sickle cell disease and management strategies. Data Source. A systematic review of pertinent original research publications, reviews, and editorials was undertaken using MEDLlNE, the Cochrane Library databases, and CINAHL from 1947 to November 2010. Search terms were [asthma] and [sickle cell disease]. Additional publications considered relevant to the sickle cell disease population of patients were identified; search terms included [sickle cell disease] combined with [acetaminophen], [pain medications], [vitamin D], [beta agonists], [exhaled nitric oxide], and [corticosteroids]. Results. The reported prevalence of asthma in children with sickle cell disease varies from 2% to approximately 50%. Having asthma increases the risk for developing acute chest syndrome , death, or painful episodes compared to having sickle cell disease without asthma. Asthma and sickle cell may be linked by impaired nitric oxide regulation, excessive production of leukotrienes, insufficient levels of Vitamin D, and exposure to acetaminophen in early life. Treatment of sickle cell patients includes using commonly prescribed asthma medications; specific considerations are suggested to ensure safety in the sickle cell population. Conclusion. Prospective controlled trials of drug treatment for asthma in patients who have both sickle cell disease and asthma are urgently needed.


Highly efficient femtosecond pulse stretching by tailoring cavity dispersion in erbium fiber lasers with an intracavity short-pass edge filter.
We demonstrate highly efficient pulse stretching in Er(3+)-doped femtosecond mode-locked fiber lasers by tailoring cavity dispersion using an intracavity short-pass edge filter. The cavity dispersion is preset at around zero to obtain the shortest pulsewidth. When the cutoff wavelength of the short-pass edge filter is thermo-optically tuned to overlap the constituting spectral components of mode-locked pulses, large negative waveguide dispersion is introduced by the steep cutoff slope and the total cavity dispersion is moved to normal dispersion regime to broaden the pulsewidth. The time-bandwidth product of the mode-locked pulse increases with the decreasing temperature at the optical liquid surrounding the short-pass edge filter. Pulse stretch ratio of 3.53 (623.8 fs/176.8 fs) can be efficiently achieved under a temperature variation of 4 °C.


WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a phase 2, randomized, double blind, placebo controlled study.
Cutaneous leishmaniasis (cl) is a disfiguring disease that confronts clinicians with a quandary: leave patients untreated or engage in a complex or toxic treatment. Topical treatment of CL offers a practical and safe option. Accordingly, the treatment of CL with WR279,396, a formulation of paromomycin and gentamicin in a hydrophilic base, was investigated in a phase 2 clinical study in Tunisia and France. A phase 2, randomized, double blind, vehicle-controlled study was conducted to assess the safety and efficacy of topical WR279,396 when applied twice a day for 20 days as treatment for parasitologically confirmed CL. The study protocol established the primary efficacy end point as complete clinical response (CCR) defined as 50% or greater reduction in the ulceration size of an index lesion by day 50 (D50) followed by complete re-epithelialization by D100, and no relapse through D180. Ninety-two subjects were randomized. Leishmania major was identified in 66 of 68 isolates typed (97%). In the intent-to-treat population, 47 of 50 WR279,396 treated participants (94%) met the definition of CCR, compared with 30 of 42 vehicle-placebo participants (71%) [p = 0.0045]. Erythema occurred in 30% and 24% of participants receiving WR279,396 and placebo, respectively [p = 0.64]. There was no clinical or laboratory evidence of systemic toxicity. Application of WR279,396 for 20 days was found to be safe and effective in treating L. major CL, and offers great potential as a new, simple, easily applicable, and inexpensive topical therapy for this neglected disease. ClinicalTrials.gov NCT00703924.


What on Earth Have We Been Burning? Deciphering Sedimentary Records of Pyrogenic Carbon.
Humans have interacted with fire for thousands of years, yet the utilization of fossil fuels marked the beginning of a new era. Ubiquitous in the environment, pyrogenic carbon (PyC) arises from incomplete combustion of biomass and fossil fuels, forming a continuum of condensed aromatic structures. Here, we develop and evaluate 14C records for two complementary PyC molecular markers, benzene polycarboxylic acids (BPCAs) and polycyclic aromatic hydrocarbons (PAHs), preserved in aquatic sediments from a suburban and a remote catchment in the United States (U.S.) from the mid-1700s to 1998. Results show that the majority of PyC stems from local sources and is transferred to aquatic sedimentary archives on subdecadal to millennial time scales. Whereas a small portion stems from near-contemporaneous production and sedimentation, the majority of PyC (∼90%) experiences delayed transmission due to "preaging" on millennial time scales in catchment soils prior to its ultimate deposition. BPCAs (soot) and PAHs (precursors of soot) trace fossil fuel-derived PyC. Both markers parallel historical records of the consumption of fossil fuels in the U.S., yet never account for more than 19% total PyC. This study demonstrates that isotopic characterization of multiple tracers is necessary to constrain histories and inventories of PyC and that sequestration of PyC can markedly lag its production.


Early events associated with infection of Epstein-Barr virus infection of primary B-cells.
Epstein Barr virus (EBV) is closely associated with the development of a vast number of human cancers. To develop a system for monitoring early cellular and viral events associated with EBV infection a self-recombining BAC containing 172-kb of the Epstein Barr virus genome BAC-EBV designated as MD1 BAC (Chen et al., 2005, J.Virology) was used to introduce an expression cassette of green fluorescent protein (GFP) by homologous recombination, and the resultant BAC clone, BAC-GFP-EBV was transfected into the HEK 293T epithelial cell line. The resulting recombinant GFP EBV was induced to produce progeny virus by chemical inducer from the stable HEK 293T BAC GFP EBV cell line and the virus was used to immortalize human primary B-cell as monitored by green fluorescence and outgrowth of the primary B cells. The infection, B-cell activation and cell proliferation due to GFP EBV was monitored by the expression of the B-cell surface antigens CD5, CD10, CD19, CD23, CD39, CD40 , CD44 and the intercellular proliferation marker Ki-67 using Flow cytometry. The results show a dramatic increase in Ki-67 which continues to increase by 6-7 days post-infection. Likewise, CD40 signals showed a gradual increase, whereas CD23 signals were increased by 6-12 hours, maximally by 3 days and then decreased. Monitoring the viral gene expression pattern showed an early burst of lytic gene expression. This up-regulation of lytic gene expression prior to latent genes during early infection strongly suggests that EBV infects primary B-cell with an initial burst of lytic gene expression and the resulting progeny virus is competent for infecting new primary B-cells. This process may be critical for establishment of latency prior to cellular transformation. The newly infected primary B-cells can be further analyzed for investigating B cell activation due to EBV infection.


Individual-specific mortality is associated with how individuals evaluate future discounting decisions.
How organisms discount the value of future rewards is associated with many important outcomes, and may be a central component of theories of life-history. According to life-history theories, prioritizing immediacy is indicative of an accelerated strategy (i.e. reaching reproductive maturity quickly and producing many offspring at the cost of long-term investment). Previous work extrapolating life-history theories to facultative calibration of life-history traits within individuals has theorized that cues to mortality can trigger an accelerated strategy; however, compelling evidence for this hypothesis in modern humans is lacking. We assessed whether country-level life expectancy predicts individual future discounting behaviour across multiple intertemporal choice items in a sample of 13 429 participants from 54 countries. Individuals in countries with lower life expectancy were more likely to prefer an immediate reward to one that is delayed. Individuals from countries with greater life expectancy were especially more willing to wait for a future reward when the relative gain in choosing the future reward was large and/or the delay period was short. These results suggest that cues to mortality can influence the way individuals evaluate intertemporal decisions, which in turn can inform life-history trade-offs. We also found that older (but not very old) participants were more willing to wait for a future reward when there is a greater relative gain and/or shorter delay period, consistent with theoretical models that suggest individuals are more future-orientated at middle age.


Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer.
Tumors evade the immune system though a myriad of mechanisms. Using checkpoint inhibitors to help reprime T cells to recognize tumor has had great success in malignancies including melanoma, lung, and renal cell carcinoma. Many tumors including prostate cancer are resistant to such treatment. However, Sipuleucel-T, a dendritic cell (DC) based immunotherapy, improved overall survival (OS) in prostate cancer. Despite this initial success, further DC vaccines have failed to progress and there has been limited uptake of Sipuleucel-T in the clinic. We know in prostate cancer (PCa) that both the adaptive and the innate arms of the immune system contribute to the immunosuppressive environment. This is at least in part due to dysfunction of DC that play a crucial role in the initiation of an immune response. We also know that there is a paucity of DC in PCa, and that those there are immature, creating a tolerogenic environment. These attributes make PCa a good candidate for a DC based immunotherapy. Ultimately, the knowledge gained by much research into antigen processing and presentation needs to translate from bench to bedside. In this review we will analyze why newer vaccine strategies using monocyte derived DC (MoDC) have failed to deliver clinical benefit, particularly in PCa, and highlight the emerging antigen loading and presentation technologies such as nanoparticles, antibody-antigen conjugates and virus co-delivery systems that can be used to improve efficacy. Lastly, we will assess combination strategies that can help overcome the immunosuppressive microenvironment of PCa.


Water extraction on Mars for an expanding human colony.
In-situ water extraction is necessary for an extended human presence on Mars. This study looks at the water requirements of an expanding human colony on Mars and the general systems needed to supply that water from the martian atmosphere and regolith. The proposed combination of systems in order to supply the necessary water includes a system similar to Honeybee Robotics' Mobile In-Situ Water Extractor (MISWE) that uses convection, a system similar to MISWE but that directs microwave energy down a borehole, a greenhouse or hothouse type system, and a system similar to the Mars Atmospheric Resource Recovery System (MARRS). It is demonstrated that a large water extraction system that can take advantage of large deposits of water ice at site specific locations is necessary to keep up with the demands of a growing colony.


Pearls: multiple sclerosis.
Multiple sclerosis (MS) affects more than 500,000 Americans, and it is commonly on the differential diagnosis associated with patient referrals to neurology offices. Diagnostically, there are several nuances to the established criteria. Understanding the usefulness of various tests and the potential diagnoses that can cause false-positives is critical when evaluating patients for possible MS. Furthermore, recognizing various possible mimics in given situations will help practitioners avoid unnecessary treatment of patients. Once diagnosed, MS patients have a multitude of possible symptoms that they can experience, and rely on their neurologists to have an understanding of the potential interventions. Finally, there are various therapies currently available for disease modification. Developing a reasonable treatment algorithm that can be applied to patients is important when presenting patients with the various options. This article summarizes some of the pearls and pitfalls associated with the evaluation and management of patients with relapsing-remitting multiple sclerosis.


Unilateral axillary Adenopathy in the setting of COVID-19 vaccine.
With the recent U.S. Food and Drug Administration (FDA)-approval and rollout of the Pfizer-BioNTech and Moderna COVID-19 vaccines, it is important for radiologists to consider recent COVID-19 vaccination history as a possible differential diagnosis for patients with unilateral axillary adenopathy. Hyperplastic axillary nodes can be seen on sonography after any vaccination but are more common after a vaccine that evokes a strong immune response, such as the COVID-19 vaccine. As the differential of unilateral axillary adenopathy includes breast malignancy, it is crucial to both thoroughly evaluate the breast for primary malignancy and to elicit history of recent vaccination. As COVID-19 vaccines will soon be available to a larger patient population, radiologists should be familiar with the imaging features of COVID-19 vaccine induced hyperplastic adenopathy and its inclusion in a differential for unilateral axillary adenopathy. Short-term follow-up for unilateral axillary adenopathy in the setting of recent COVID-19 vaccination is an appropriate recommendation, in lieu of immediately performing potentially unnecessary and costly axillary lymph node biopsies.


Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma.
Recombinant HSP70 chaperone exerts a profound anticancer effect when administered intratumorally. This action is based on the ability of HSP70 to penetrate tumor cells and extract its endogenous homolog. To enhance the efficacy of HSP70 cycling, we employed phloretin, a flavonoid that enhances the pore-forming activity of the chaperone on artificial membranes. Phloretin increased the efficacy of HSP70 penetration in B16 mouse melanoma cells and K-562 human erythroblasts; this was accompanied with increased transport of the endogenous HSP70 to the plasma membrane. Importantly, treatment with HSP70 combined with phloretin led to the elevation of cell sensitivity to cytotoxic lymphocytes by 16-18 % compared to treatment with the chaperone alone. The incubation of K-562 cells with biotinylated HSP70 and phloretin increased the amount of the chaperone released from cells, suggesting that chaperone cycling could trigger a specific anti-tumor response. We studied the effect of the combination of HSP70 and phloretin using B16 melanoma and a novel method of HSP70-gel application. We found that the addition of phloretin to the gel reduced tumor weight almost fivefold compared with untreated mice, while the life span of the animals extended from 25 to 39 days. The increased survival was corroborated by the activation of innate and adaptive immunity; interestingly, HSP70 was more active in induction of CD8+ cell-mediated toxicity and γIFN production while phloretin contributed largely to the CD56+ cell response. In conclusion, the combination of HSP70 with phloretin could be a novel treatment for efficient immunotherapy of intractable cancers such as skin melanoma.


Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome.
To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.