Mitigating Impacts of the COVID-19 Pandemic on Gorilla Conservation: Lessons From Bwindi Impenetrable Forest, Uganda.
The COVID-19 pandemic, affecting all countries, with millions of cases and deaths, and economic disruptions due to lockdowns, also threatens the health and conservation of endangered mountain gorillas. For example, increased poaching due to absence of tourism income, led to the killing on 1st June 2020 of a gorilla by a hungry community member hunting duiker and bush pigs. Conservation Through Public Health (CTPH), a grassroots NGO and non-profit founded in 2003 promotes biodiversity conservation by enabling people to co-exist with wildlife through integrated programs that improve animal health, community health, and livelihoods in and around Africa's protected areas and wildlife rich habitats. Through these programs, we have helped to mitigate these impacts. CTPH worked with Uganda Wildlife Authority and other NGOs to improve great ape viewing guidelines and prevent transmission of COVID-19 between people and gorillas. Park staff, Gorilla Guardians herding gorillas from community land to the park and Village Health and Conservation Teams were trained to put on protective face masks, enforce hand hygiene and a 10-meter great ape viewing distance. To reduce the communities' need to poach, CTPH found a UK-based distributor, for its Gorilla Conservation Coffee social enterprise enabling coffee farmers to earn revenue in the absence of tourism and provided fast growing seedlings to reduce hunger in vulnerable community members. Lessons learned show the need to support non-tourism dependent community livelihoods, and more responsible tourism to the great apes, which CTPH is advocating to governments, donors and tour companies through an Africa CSO Biodiversity Alliance policy brief.


Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.
In Drosophila and Caenorhabditis elegans, kinase suppressor of ras (KSR) positively modulates Ras/Raf-mitogen-activated protein kinase (MAPK) signaling. The precise signaling mechanism of mammalian KSR1 and its role in Ras-mediated transformation, however, remain uncertain. To gain insight into KSR1 function in vivo, we generated mice homozygous null for KSR1. ksr1-/- mice are viable and without major developmental defects. However, an unusual disorganized hair follicle phenotype manifest in epidermal growth factor receptor knockout mice is recapitulated in ksr1-/- mice, providing genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals. Furthermore, ksr1-/- mice allow for the definition of KSR1-dependent and -independent mechanisms of c-Raf-1 activation. In embryonic fibroblasts, epidermal growth factor and 12-O-tetradecanoylphorbol-13-acetate activated the MAPK cascade to a similar extent, yet only c-Raf-1 activation by epidermal growth factor depended on KSR1. Moreover, whereas the genesis of polyomavirus middle T antigen (MT)-driven mammary cancer appears independent of KSR1, KSR1 is obligate for v-Ha-ras-mediated skin tumor formation. The growth of MT-driven mammary tumor was moderately slowed in ksr1-/- mice, however, consistent with a decreased rate of proliferation of ksr1-/- cells (T cells and embryonic fibroblasts). Nonetheless, all ksr1-/- animals succumbed to mammary cancer. In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1-/- background. Hence, MT-driven mammary tumor genesis, which is signaled through src and phosphatidylinositol 3'-kinase, appears KSR1 independent, whereas v-Ha-ras-mediated skin cancer, signaled through the Raf-1/MAPK cascade, requires KSR1. These results suggest KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis.


Peripheral vascular responses during carotid baroreceptor stimulation in normotensive and hypertensive subjects.
1. The carotid baroreceptors were stimulated for 2 min by neck suction at -30 and -60 mmHg in 19 normotensive subjects and 12 patients with moderate essential hypertension. 2. Blood pressure was measured with a mercury sphygmomanometer and heart rate was derived from beat-to-beat analysis of the electrocardiogram. Blood flow was measured simultaneously at calf and finger with venous occlusion plethysmography and the vascular resistance was calculated. 3. During neck suction at -30 and -60 mmHg there was a significant decrease in arterial blood pressure and heart rate. There was a transient vasodilatation of the calf blood vessels, while there was a sustained vasoconstriction of the finger blood vessels. These results were qualitatively similar in both groups; however, there were quantitative differences. 4. These experiments show that there is a selective autonomic control of the different peripheral vascular beds by the carotid baroreceptors in both normotension and mild essential hypertension.


A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis.
This study was initiated to test the hypothesis that treatment with clomiphene citrate (CC) and intrauterine insemination (IUI) results in increased fecundity when compared with periovulatory intercourse in couples with either unexplained infertility or surgically corrected endometriosis. Sixty-seven couples entered a randomized, prospective trial comparing CC/IUI with observation. During the study, there were 14 pregnancies in 148 treated cycles (fecundity = 0.095) compared with 5 pregnancies in 150 untreated cycles (fecundity = 0.033). Using life-table analysis and the log-rank test, the difference in fecundities was statistically significant. Pregnancy outcome was not significantly different between the two groups. When comparing conception with nonconception cycles during treatment, no differences between the size of the lead follicle or the number of dominant follicles was detected. We conclude that treatment with CC/IUI improves fecundity in couples with unexplained infertility or surgically corrected endometriosis.


Functional hemispherotomy for epilepsy in the very young.
Epilepsy is one of the most common neurological disorders in children. Among very young children, one-third are resistant to medical treatment, and lack of effective treatment may result in adverse outcomes. Although functional hemispherotomy is an established treatment for epilepsy, its outcome in the very young child has not been widely reported. In this study the authors investigated seizure and developmental results after hemispherotomy in children younger than 3 years. The authors reviewed a prospective database of all children younger than 3 years with medically intractable epilepsy who underwent functional hemispherotomy at the authors' institution during the period between 2012 and 2020. Demographic data, epilepsy history, underlying etiology, operative and transfusion details, and seizure and developmental outcomes were analyzed. Twelve patients were included in this study. The mean age (± SD) at seizure onset was 3 ± 2.6 months and at surgery was 1.3 ± 0.77 years, with a mean follow-up of 4 years. Diagnoses included hemimegalencephaly (n = 5), hemidysplasia (n = 2), hypoxic/hemorrhagic (n = 2), traumatic (n = 1), Sturge-Weber syndrome (n = 1), and mild hemispheric structural abnormality with EEG/PET correlates (n = 1). Eleven patients achieved an Engel class I outcome, and 1 patient achieved Engel class IV at last follow-up. No deaths, infections, cerebrovascular events, or unexpected long-term neurological deficits were recorded. All children progressed neurodevelopmentally following surgery, but their developmental levels remained behind their chronological age, with an overall mean composite Vineland Adaptive Behavior Scale score of 58 (normal: 86-114, low: < 70). One patient required insertion of a subdural peritoneal shunt, 1 patient required dural repair for a CSF fluid leak, and 1 patient required aspiration of a pseudomeningocele. In 2 patients, both of whom weighed less than 5.7 kg, the first operation was incomplete due to blood loss. Hemispherotomy in children younger than 3 years offers excellent seizure control and an acceptable risk-to-benefit ratio in well-selected patients. Families of children weighing less than 6 kg should be counseled regarding the possibility of staged surgery. Postoperatively, children continue to make appropriate, despite delayed, developmental progress.


DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS.
Rubinstein-Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation. The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date. Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated. We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS ("moderate or incomplete RSTS", detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H. We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS. Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.


A multidrug resistance plasmid contains the molecular switch for type VI secretion in Acinetobacter baumannii.
Infections with Acinetobacter baumannii, one of the most troublesome and least studied multidrug-resistant superbugs, are increasing at alarming rates. A. baumannii encodes a type VI secretion system (T6SS), an antibacterial apparatus of Gram-negative bacteria used to kill competitors. Expression of the T6SS varies among different strains of A. baumannii, for which the regulatory mechanisms are unknown. Here, we show that several multidrug-resistant strains of A. baumannii harbor a large, self-transmissible resistance plasmid that carries the negative regulators for T6SS. T6SS activity is silenced in plasmid-containing, antibiotic-resistant cells, while part of the population undergoes frequent plasmid loss and activation of the T6SS. This activation results in T6SS-mediated killing of competing bacteria but renders A. baumannii susceptible to antibiotics. Our data show that a plasmid that has evolved to harbor antibiotic resistance genes plays a role in the differentiation of cells specialized in the elimination of competing bacteria.


Fracture through a geode in the proximal ulna.
Chronic joint pain in rheumatoid arthritis may mask that from other causes. Stress fractures, particularly in osteoporotic lower limb bones of such patients, are well described but can still cause diagnostic difficulty. These difficulties were highlighted by a case in which an unusual fracture occurred through a geode in the proximal ulna mimicking an exacerbation of synovitis in the elbow joint.


Investigating the formation and consolidation of incidentally learned trust.
People make inferences about the trustworthiness of others based on their observed gaze behavior. Faces that consistently look toward a target location are rated as more trustworthy than those that look away from the target. Representations of trust are important for future interactions; yet little is known about how they are consolidated in long-term memory. Sleep facilitates memory consolidation for incidentally learned information and may therefore support the retention of trust representations. We investigated the consolidation of trust inferences across periods of sleep or wakefulness. In addition, we employed a memory cueing procedure (targeted memory reactivation [TMR]) in a bid to strengthen certain trust memories over others. We observed no difference in the retention of trust inferences following delays of sleep or wakefulness, and there was no effect of TMR in either condition. Interestingly, trust inferences remained stable 1 week after learning, irrespective of the initial postlearning delay. A second experiment showed that this implicit learning occurs despite participants' being unable to explicitly recall the gaze behavior of specific faces immediately after encoding. Together, these results suggest that gist-like, social inferences are formed at the time of learning without retaining the original episodic memory and thus do not benefit from offline consolidation through replay. We discuss our findings in the context of a novel framework whereby trust judgments reflect an efficient, powerful, and adaptable storage device for social information. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Incidence, etiopathogenesis and pathological aspects of genitourinary tuberculosis in India: A journey revisited.
Tuberculosis is one of the major health problems in India. Genitourinary tuberculosis comprises 20% of all extrapulmonary tuberculosis, and is the most common extrapulmonary system to be affected by this disease. The recent surge in the incidence of HIV-infected patients in India has further ignited the fury. Though the members of the Mycobacterium species are well identified, the incidence could not be controlled due to its complex etiopathogenesis and genetic background. The spectrum of pathological changes of genitourinary tuberculosis is wide, which varies from normal morphology to markedly scarred kidney, bladder, and epididymis with autocystectomy. A thorough knowledge is required to prevent the end-stage complications. The sequel can be detrimental for the patient's physical, behavioral, psychological, and financial health. Though culture and polymerase chain reaction are available for the detection of tuberculosis, the sensitivity and specificity varies widely and one should be aware. A thorough knowledge of epidemiology, immunopathogenesis, spectrum of the disease and the possible sequels, will help better and effective management of the disease.


Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme.
Glioblastoma multiforme is the most common tumor arising in the central nervous system. Patients with these tumors have limited treatment options and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment, however the use of these will require a fuller understanding of the genetic changes in these complex tumors. In this study, we identify copy number changes in a series of glioblastoma multiforme tumors and cell lines by applying high-resolution microarray comparative genomic hybridization. Molecular cytogenetic characterization of the cell lines revealed that copy number changes define translocation breakpoints. We focused on chromosome 6 and further characterized three regions of copy number change associated with translocations including a discrete deletion involving IGF2R, PARK2, PACRG and QKI and an unbalanced translocation involving POLH, GTPBP2 and PTPRZ1.


Phase-field-crystal study of solute trapping.
In this study we have incorporated two time scales into the phase-field-crystal model of a binary alloy to explore different solute trapping properties as a function of crystal-melt interface velocity. With only diffusive dynamics, we demonstrate that the segregation coefficient, K as a function of velocity for a binary alloy is consistent with the model of Kaplan and Aziz where K approaches unity in the limit of infinite velocity. However, with the introduction of wavelike dynamics in both the density and concentration fields, the trapping follows the kinetics proposed by Sobolev [Phys. Lett. A 199, 383 (1995)], where complete trapping occurs at a finite velocity.


Essential oil variability in natural populations of Picea omorika, a rare European conifer.
This study is the first report on the composition and variability of essential oil in the relic, endemic, and vulnerable tree species Serbian spruce, Picea omorika, in its natural populations. In the needles of 108 trees of four natural populations, 49 components of essential oils were identified. The main compounds were bornyl acetate (29.2%), camphene (18.7%), and alpha-pinene (12.9%). Fourteen additional components had the contents of up to 0.5%: alpha-cadinol (6.1%), limonene (5.8%), santene (3.5%), (E)-hex-2-enal (2.9%), T-cadinol (2.9%), delta-cadinene (2.3%), tricyclene (2.1%), myrcene (1.6%), beta-pinene (1.2%), borneol (0.9%), germacrene D (0.9%), alpha-muurolene (0.6%), and two unidentified compounds. Population IV from Milesevka Canyon had a much higher content of bornyl acetate (42.9%). Populations I-III from Mt. Tara were more abundant in sesquiterpenes (up to 18.2%). The content of bornyl acetate, the multi-variation analyses according to seven selected components, especially the cluster analysis and genetic analysis of alpha-cadinol, which suggested the monogenic type of heredity, showed a clear differentiation of the two geographic areas, the similarity of populations I-III from the area of Mt. Tara, and the separation of the population IV from Milesevka Canyon.


DHA-Induced Perturbation of Human Serum Metabolome. Role of the Food Matrix and Co-Administration of Oat β-glucan and Anthocyanins.
Docosahexaenoic acid (DHA) has been reported to have a positive impact on many diet-related disease risks, including metabolic syndrome. Although many DHA-enriched foods have been marketed, the impact of different food matrices on the effect of DHA is unknown. As well, the possibility to enhance DHA effectiveness through the co-administration of other bioactives has seldom been considered. We evaluated DHA effects on the serum metabolome administered to volunteers at risk of metabolic syndrome as an ingredient of three different foods. Foods were enriched with DHA alone or in combination with oat beta-glucan or anthocyanins and were administered to volunteers for 4 weeks. Serum samples collected at the beginning and end of the trial were analysed by NMR-based metabolomics. Multivariate and univariate statistical analyses were used to characterize modifications in the serum metabolome and to evaluate bioactive-bioactive and bioactive-food matrix interactions. DHA administration induces metabolome perturbation that is influenced by the food matrix and the co-presence of other bioactives. In particular, when co-administered with oat beta-glucan, DHA induces a strong rearrangement in the lipoprotein profile of the subjects. The observed modifications are consistent with clinical results and indicate that metabolomics represents a possible strategy to choose the most appropriate food matrices for bioactive enrichment.


Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.
The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.


Neural mechanisms of affective matching across faces and scenes.
The emotional matching paradigm, introduced by Hariri and colleagues in 2000, is a widely used neuroimaging experiment that reliably activates the amygdala. In the classic version of the experiment faces with negative emotional expression and scenes depicting distressing events are compared with geometric shapes instead of neutral stimuli of the same category (i.e. faces or scenes). This makes it difficult to clearly attribute amygdala activation to the emotional valence and not to the social content. To improve this paradigm, we conducted a functional magnetic resonance imaging study in which emotionally neutral and, additionally, positive stimuli within each stimulus category (i.e. faces, social and non-social scenes) were included. These categories enabled us to differentiate the exact nature of observed effects in the amygdala. First, the main findings of the original paradigm were replicated. Second, we observed amygdala activation when comparing negative to neutral stimuli of the same category. However, for negative faces, the amygdala response habituated rapidly. Third, positive stimuli were associated with widespread activation including the insula and the caudate. This validated adaption study enables more precise statements on the neural activation underlying emotional processing. These advances may benefit future studies on identifying selective impairments in emotional and social stimulus processing.


Predictive model for long-term patient satisfaction after surgery for grade I degenerative lumbar spondylolisthesis: insights from the Quality Outcomes Database.
OBJECTIVESince the enactment of the Affordable Care Act in 2010, providers and hospitals have increasingly prioritized patient-centered outcomes such as patient satisfaction in an effort to adapt the "value"-based healthcare model. In the current study, the authors queried a prospectively maintained multiinstitutional spine registry to construct a predictive model for long-term patient satisfaction among patients undergoing surgery for Meyerding grade I lumbar spondylolisthesis.METHODSThe authors queried the Quality Outcomes Database for patients undergoing surgery for grade I lumbar spondylolisthesis between July 1, 2014, and June 30, 2016. The primary outcome of interest for the current study was patient satisfaction as measured by the North American Spine Surgery patient satisfaction index, which is measured on a scale of 1-4, with 1 indicating most satisfied and 4 indicating least satisfied. In order to identify predictors of higher satisfaction, the authors fitted a multivariable proportional odds logistic regression model for ≥ 2 years of patient satisfaction after adjusting for an array of clinical and patient-specific factors. The absolute importance of each covariate in the model was computed using an importance metric defined as Wald chi-square penalized by the predictor degrees of freedom.RESULTSA total of 502 patients, out of a cohort of 608 patients (82.5%) with grade I lumbar spondylolisthesis, undergoing either 1- or 2-level decompression (22.5%, n = 113) or 1-level decompression and fusion (77.5%, n = 389), met the inclusion criteria; of these, 82.1% (n = 412) were satisfied after 2 years. On univariate analysis, satisfied patients were more likely to be employed and working (41.7%, n = 172, vs 24.4%, n = 22; overall p = 0.001), more likely to present with predominant leg pain (23.1%, n = 95, vs 11.1%, n = 10; overall p = 0.02) but more likely to present with lower Numeric Rating Scale score for leg pain (median and IQR score: 7 [5-9] vs 8 [6-9]; p = 0.05). Multivariable proportional odds logistic regression revealed that older age (OR 1.57, 95% CI 1.09-2.76; p = 0.009), preoperative active employment (OR 2.06, 95% CI 1.27-3.67; p = 0.015), and fusion surgery (OR 2.3, 95% CI 1.30-4.06; p = 0.002) were the most important predictors of achieving satisfaction with surgical outcome.CONCLUSIONSCurrent findings from a large multiinstitutional study indicate that most patients undergoing surgery for grade I lumbar spondylolisthesis achieved long-term satisfaction. Moreover, the authors found that older age, preoperative active employment, and fusion surgery are associated with higher odds of achieving satisfaction.


Morphological and Molecular Characterization of Longidorus americanum n. sp. (Nematoda: Longidoridae), a Needle Nematode Parasitizing Pine in Georgia.
We describe and illustrate a new needle nematode, Longidorus americanum n. sp., associated with patches of severely stunted and chlorotic loblolly pine, (Pinus taeda L.) seedlings in seedbeds at the Flint River Nursery (Byromville, GA). It is characterized by having females with a body length of 5.4-9.0 mm; lip region slightly swollen, anteriorly flattened, giving the anterior end a truncate appearance; long odontostyle (124-165 microm); vulva at 44%-52% of body length; and tail conoid, bluntly rounded to almost hemispherical. Males are rare but present, and in general shorter than females. The new species is morphologically similar to L. biformis, L. paravineacola, L. saginus, and L. tarjani but differs from these species either by the body, odontostyle and total stylet length, or by head and tail shape. Sequence data from the D2-D3 region of the 28S rDNA distinguishes this new species from other Longidorus species. Phylogenetic relationships of Longidorus americanum n. sp. with other longidorids based on analysis of this DNA fragment are presented. Additional information regarding the distribution of this species within the region is required.


Sodium chloride toxicity and the cellular basis of salt tolerance in halophytes.
Halophytes are the flora of saline soils. They adjust osmotically to soil salinity by accumulating ions and sequestering the vast majority of these (generally Na(+) and Cl(-)) in vacuoles, while in the cytoplasm organic solutes are accumulated to prevent adverse effects on metabolism. At high salinities, however, growth is inhibited. Possible causes are: toxicity to metabolism of Na(+) and/or Cl(-) in the cytoplasm; insufficient osmotic adjustment resulting in reduced net photosynthesis because of stomatal closure; reduced turgor for expansion growth; adverse cellular water relations if ions build up in the apoplast (cell walls) of leaves; diversion of energy needed to maintain solute homeostasis; sub-optimal levels of K(+) (or other mineral nutrients) required for maintaining enzyme activities; possible damage from reactive oxygen species; or changes in hormonal concentrations. This review discusses the evidence for Na(+) and Cl(-) toxicity and the concept of tissue tolerance in relation to halophytes. The data reviewed here suggest that halophytes tolerate cytoplasmic Na(+) and Cl(-) concentrations of 100-200 mm, but whether these ions ever reach toxic concentrations that inhibit metabolism in the cytoplasm or cause death is unknown. Measurements of ion concentrations in the cytosol of various cell types for contrasting species and growth conditions are needed. Future work should also focus on the properties of the tonoplast that enable ion accumulation and prevent ion leakage, such as the special properties of ion transporters and of the lipids that determine membrane permeability.


A dorsal visual route necessary for global form perception: evidence from neuropsychological fMRI.
Hierarchical models of visual processing assume that global pattern recognition is contingent on the progressive integration of local elements across larger spatial regions, operating from early through intermediate to higher-level cortical regions. Here, we present results from neuropsychological fMRI that refute such models. We report two patients, one with lesions to intermediate ventral regions and the other with damage around the intraparietal sulcus (IPS). The patient with ventral damage showed normal behavioral and BOLD responses to global Glass patterns. The patient with IPS damage was impaired in discriminating global patterns and showed a lack of significant responses to these patterns in intermediate visual regions spared by the lesion. However, this patient did show BOLD activity to translational patterns, where local element relations are important. These results suggest that activation of intermediate ventral regions is not necessary to code global patterns; instead global patterns are coded in a heterarchical fashion. High-level regions of dorsal cortex are necessary to generate global pattern coding in intermediate ventral regions; in contrast, local integration processes are not sufficient.


Genetic characterization of blaNDM-harboring plasmids in carbapenem-resistant Escherichia coli from Myanmar.
The bacterial enzyme New Delhi metallo-β-lactamase hydrolyzes almost all β-lactam antibiotics, including carbapenems, which are drugs of last resort for severe bacterial infections. The spread of carbapenem-resistant Enterobacteriaceae that carry the New Delhi metallo-β-lactamase gene, blaNDM, poses a serious threat to public health. In this study, we genetically characterized eight carbapenem-resistant Escherichia coli isolates from a tertiary care hospital in Yangon, Myanmar. The eight isolates belonged to five multilocus-sequence types and harbored multiple antimicrobial-resistance genes, resulting in resistance against nearly all of the antimicrobial agents tested, except colistin and fosfomycin. Nine plasmids harboring blaNDM genes were identified from these isolates. Multiple blaNDM genes were found in the distinct Inc-replicon types of the following plasmids: an IncA/C2 plasmid harboring blaNDM-1 (n = 1), IncX3 plasmids harboring blaNDM-4 (n = 2) or blaNDM-7 (n = 1), IncFII plasmids harboring blaNDM-4 (n = 1) or blaNDM-5 (n = 3), and a multireplicon F plasmid harboring blaNDM-5 (n = 1). Comparative analysis highlighted the diversity of the blaNDM-harboring plasmids and their distinct characteristics, which depended on plasmid replicon types. The results indicate circulation of phylogenetically distinct strains of carbapenem-resistant E. coli with various plasmids harboring blaNDM genes in the hospital.


Ventilatory effects of hypoxia and adenosine infusion in patients after bilateral carotid endarterectomy.
1. We have studied the carotid body contribution to hypoxic respiratory drive, using a hypoxic/hyperoxic switching technique, and the ventilatory response to intravenous infusion of adenosine, a recently described respiratory stimulant, in five patients with bilateral carotid endarterectomy. 2. The contribution made by the carotid bodies to total ventilatory drive during hypoxia varied from 2.5% to 45.9%. 3. The ventilatory response to adenosine infusion varied from a 7% decrease to a 25% increase in ventilation. 4. Those patients with intact hypoxic ventilatory drive showed respiratory stimulation, whereas of the two patients with attenuated chemoreflexes, one showed no stimulation and the other depression of ventilation in response to adenosine infusion. 5. We conclude that adenosine exerts its respiratory stimulant effect via an action on the peripheral chemoreceptors. This may coexist with a centrally mediated respiratory depression that is masked when the carotid bodies are intact.


Incidence and pattern of jaundice in healthy breast-fed infants during the first month of life.
The incidence and pattern of jaundice in 155 normal, full-term, breast-fed, white infants was examined. Infants were screened for jaundice on Days 2, 3, 5, 7, 9, 11, and 13 following birth using transcutaneous bilirubinometry (TcB). By Day 3, 49.7% of the infants were classified as jaundiced (> 10 mg/dl). Infants with low TcB indices on Days 2, 3, and 5 never developed jaundice as indicated by elevated TcB indices on Days 7, 9, 11, and 13. Hence, it may be possible to target infants at risk for severe jaundice prior to discharge. The observed rate of 10.3% for breast-milk jaundice (jaundice present at Day 13) is significantly higher than the highest reported rate of 2.4% (z = 6.43, p < .01). Furthermore, the pattern of jaundice in these infants does not appear to have two peaks, indicating that it is not possible to distinguish between exaggerated physiologic jaundice and breast-milk jaundice using TcB.


Poverty, out-of-pocket payments and access to health care: evidence from Tajikistan.
Most countries of the Former Soviet Union (FSU) have either initiated or are contemplating reform of the health sector. With negative real income growth and falling government revenues, a key concern of many governments is to secure additional finance through non-budgetary sources such as hypothecated payroll taxes, voluntary insurance, and increased private finance through patient cost-sharing. However, before such reforms can be considered, information is needed both on the current levels and distribution of household expenditures on health care, and the extent to which increased charges may affect access to health services, especially amongst the poor. This paper uses the Tajikistan Livings Standard Survey to investigate the level and distribution of out-of-pocket payments for health care in Tajikistan and to examine the extent to which such payments act as barriers to health-care access. The data show that there are significant differences in health-care utilisation rates across socio-economic groups and that these differences are related to ability to pay. Official and informal payments are acting both to deter people from seeking medical assistance and once advice has been sought, from receiving the most appropriate treatment. Despite informal exemptions, out-of-pocket payments for health care are exacting a high toll on household welfare with households being forced to sell assets or go into debt to meet the costs of care. Urgent action is needed to ensure equity in access to health care.


Aspirin sensitivity does not compromise quality-of-life outcomes in patients with Samter's triad.
To demonstrate that quality-of-life outcomes after endoscopic sinus surgery are not compromised in patients with Samter's triad (asthma, nasal polyps, aspirin sensitivity) when compared to patients with eosinophilic chronic rhinosinusitis with nasal polyposis (eCRSwP) who are not aspirin sensitive. Retrospective review of prospectively collected data. Thirty-two patients with Samter's triad were identified from a prospectively collected patient database from 2003 to 2012. Preoperative and postoperative symptom and endoscopy scores were compared to those of 37 consecutive patients with eCRSwP who were not aspirin sensitive (control). Student t test and Fisher exact test were used to examine for differences between the two groups. Symptom scores were assessed using the 20-item Sino-Nasal Outcome Test (SNOT-20). Endoscopy findings were scored according to the Lund-Kennedy methodology. Samter's triad patients had significantly worse disease preoperatively when compared to the control group: SNOT-20 (31.1 vs. 22.1, P = .004), endoscopy score (10.9 vs. 7.6, P = .0005), and Lund-Mackay computed tomography score (18.9 vs. 13.9, P = .0001). Although postoperative endoscopy scores remained worse in the Samter's triad group, postoperative SNOT-20 scores were comparable to those of the control group at ≥ 3 years follow-up (22.8 vs. 17.3, P = .43). Although Samter's triad patients present with more severe disease and are more likely to undergo revision surgery, they have postoperative quality-of-life outcomes that are comparable to patients with eCRSwP who are not aspirin sensitive. This is the first study to utilize a disease-specific, validated outcomes instrument in comparing Samter's triad patients with aspirin-tolerant patients who have nasal polyposis and tissue eosinophilia.


Metathesis of Mg2FeH6 and LiNH2 leading to hydrogen production at low temperatures.
Mg2FeH6 with a purity of up to 94.5 wt% was synthesized and its interaction with LiNH2 was investigated in this study. It was found that Li4FeH6, normally synthesized by hydriding a mixture of LiH and Fe at 700 °C and 5.5 GPa H2 pressure, can be formed via ball-milling Mg2FeH6 and LiNH2 under ambient conditions following the reaction of Mg2FeH6 + 4LiNH2 → Li4FeH6 + 2Mg(NH2)2, ΔH = -92.8 kJ mol-1. The formation of Li4FeH6 was confirmed by XRD, FTIR and Mössbauer spectroscopic characterization. Li4FeH6 further reacts with 2Mg(NH2)2 releasing ca. 4.8 wt% H2 at 225 °C and reabsorbing 3.7 wt% H2 at 200 °C and 50 bar H2 pressure. Mg(NH2)2, LiH and Fe are the hydrogenated products.


Second-line therapy in diffuse large B-cell lymphoma (DLBCL): treatment patterns and outcomes in older patients receiving outpatient chemotherapy.
Using SEER-Medicare linked data we identified elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) between January 2000 and December 2007 who received second-line outpatient chemotherapy for relapsed or refractory disease. Second-line regimens were classified into three mutually exclusive groups: aggressive, conventional, and palliative. Of the 632 (426 relapsed, 206 refractory) patients in the cohort, 27.8% received aggressive second-line therapy, 39.1% received conventional therapy, and 33.1% received palliative therapy. There were no differences in survival by type of therapy received, either for relapsed or refractory patients, although the patient risk profile differed significantly. However, duration of remission, male gender, and anemia at diagnosis were important predictors in relapsed patients, and male gender, B-symptoms, comorbidity burden, and poverty status were important predictors in refractory patients. Survival in elderly patients receiving second-line therapy remains poor, and the 24-month cost of all care exceeds $97,000. Patients would benefit from improved treatment options.


Neural correlates of the LSD experience revealed by multimodal neuroimaging.
Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.


Effects of Respiratory Motion on Y-90 PET Dosimetry for SIRT.
Respiratory motion degrades the quantification accuracy of PET imaging by blurring the radioactivity distribution. In the case of post-SIRT PET-CT verification imaging, respiratory motion can lead to inaccuracies in dosimetric measures. Using an anthropomorphic phantom filled with 90Y at a range of clinically relevant activities, together with a respiratory motion platform performing realistic motions (10-15 mm amplitude), we assessed the impact of respiratory motion on PET-derived post-SIRT dosimetry. Two PET scanners at two sites were included in the assessment. The phantom experiments showed that device-driven quiescent period respiratory motion correction improved the accuracy of the quantification with statistically significant increases in both the mean contrast recovery (+5%, p = 0.003) and the threshold activities corresponding to the dose to 80% of the volume of interest (+6%, p < 0.001). Although quiescent period gating also reduces the number of counts and hence increases the noise in the PET image, its use is encouraged where accurate quantification of the above metrics is desired.


Anti-inflammatory cytokines induce lipopolysaccharide tolerance in human monocytes without modifying toll-like receptor 4 membrane expression.
Toll-like receptor 4 (TLR4) participates in innate immunity by detecting lipopolysaccharides (LPS) of Gram-negative bacterial cell walls. TLR4 macrophage expression in mice is modulated by LPS. This fact constitutes, at least partially, the molecular basis for LPS tolerance. Very recently, the effect of interferon-gamma (IFN-gamma), a pro-inflammatory cytokine, has been described on TLR4 membrane expression of human monocytes. IFN-gamma up-regulates TLR4 expression and antagonizes the LPS-induced TLR4 down-regulation. These data prompted us to study the expression of membrane TLR4 in human mono- cytes in which LPS tolerance was induced by LPS and by anti-inflammatory cytokines [interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1)]. Data concerning this latter model, and more specifically, the effect of anti-inflammatory cytokines over TLR4 expression, are not available at present. We show here that membrane TLR4 expression in human monocytes falls after LPS exposure. The effect was prolonged for 12 h, but then expression returned to normal levels. The incubation of human monocytes with IL-10, TGFbeta1 or a mixture of both induces no alterations in membrane TLR4 expression. However, these cytokines are able to substitute the tolerizing LPS exposure in order to induce LPS tolerance. Our data help to achieve a better understanding of the way cytokines control the cellular expression of TLR.


Associations between unmet palliative care needs and cognitive impairment in a sample of diverse, community-based older adults.
Given a large number of community-based older adults with mild cognitive impairment, it is essential to better understand the relationship between unmet palliative care (PC) needs and mild cognitive impairment in community-based samples. Participants consisted of adults ages 60+ receiving services at senior centers located in New York City. The Montreal Cognitive Assessment (MoCA) and the Unmet Palliative Care Needs screening tool were used to assess participants' cognitive status and PC needs. Our results revealed a quadratic relationship between unmet PC needs and mild cognitive impairment, controlling for gender, living status, and age. Participants with either low or high MoCA scores reported lower PC needs than participants with average MoCA scores, mean difference of the contrast (low and high vs. middle) = 2.15, P = 0.08. This study is a first step toward elucidating the relationship between cognitive impairment and PC needs in a diverse community sample of older adults. More research is needed to better understand the unique PC needs of older adults with cognitive impairment living in the community.


The dark core of personality.
Many negatively connoted personality traits (often termed "dark traits") have been introduced to account for ethically, morally, and socially questionable behavior. Herein, we provide a unifying, comprehensive theoretical framework for understanding dark personality in terms of a general dispositional tendency of which dark traits arise as specific manifestations. That is, we theoretically specify the common core of dark traits, which we call the Dark Factor of Personality (D). The fluid concept of D captures individual differences in the tendency to maximize one's individual utility-disregarding, accepting, or malevolently provoking disutility for others-accompanied by beliefs that serve as justifications. To critically test D, we unify and extend prior work methodologically and empirically by considering a large number of dark traits simultaneously, using statistical approaches tailored to capture both the common core and the unique content of dark traits, and testing the predictive validity of both D and the unique content of dark traits with respect to diverse criteria including fully consequential and incentive-compatible behavior. In a series of four studies (N > 2,500), we provide evidence in support of the theoretical conceptualization of D, show that dark traits can be understood as specific manifestations of D, demonstrate that D predicts a multitude of criteria in the realm of ethically, morally, and socially questionable behavior, and illustrate that D does not depend on any particular indicator variable included. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Outcome predictors and spectrum of treatment eligibility with prospective protocolized management of intracerebral hemorrhage.
Risk predictors, spectrum of treatment eligibility, and range of expected outcomes have not been validated in consecutive series including all cases of intracerebral hemorrhage (ICH) subjected to a prospective management protocol based on current guidelines. Eighty-six cases of ICH were prospectively identified in conjunction with screening for a clinical trial during an 18-month period. All patients were subjected to protocolized management based on published "best practice" guidelines for ICH. Medical records were reviewed by trained researchers, and outcomes were assessed at various time points including latest follow-up (range, 0-24 months; mean, 3.97 months). Initial assessment parameters, treatment eligibility, and outcomes were based on standardized criteria. In accordance with past literature, mortality and functional outcomes were significantly worse in older patients, those with a larger ICH volume, and worse Glasgow Coma Scale scores, in univariate and multivariate models. The presence and severity of associated intraventricular hemorrhage also correlated with mortality and outcome. Significantly lower mortality (P = 0.024) and better functional outcomes (P = 0.018) were achieved at 30 days in patients with an ICH volume of less than 30 cm in this series than in previously published community-based historical controls without protocolized care. A tight correspondence between treatment eligibility and treatment administered was found. Previous estimates of poorer outcome in patients with ICH might not apply to contemporary management protocols, especially in patients with a smaller ICH volume. Outcome ranges in various risk categories and modeling of treatment eligibility will help project more realistic prognostication and assist with the design of future trials.


Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.
Bone marrow-derived cells contribute to tumor angiogenesis. Here, we demonstrate that monocytes expressing the Tie2 receptor (Tie2-expressing monocytes [TEMs]) (1) are a distinct hematopoietic lineage of proangiogenic cells, (2) are selectively recruited to spontaneous and orthotopic tumors, (3) promote angiogenesis in a paracrine manner, and (4) account for most of the proangiogenic activity of myeloid cells in tumors. Remarkably, TEM knockout completely prevented human glioma neovascularization in the mouse brain and induced substantial tumor regression. Besides TEMs and endothelial cells (ECs), Tie2 expression distinguished a rare population of tumor stroma-derived mesenchymal progenitors representing a primary source of tumor pericytes. Therefore, Tie2 expression characterizes three distinct cell types required for tumor neovascularization: ECs, proangiogenic cells of hematopoietic origin, and pericyte precursors of mesenchymal origin.


Male or female, we will create them: the ethics of sex selection for non-medical reasons.
The article examines the arguments for and against the practice of sex selection for non-medical reasons (e.g. parental preferences, family balancing, religious reasons) in light of the new technology of Preimplantation Genetic Diagnosis (PGD). It distinguishes between arguments about the risks to the future child, the mother and society, on the one hand, and the inherent wrongness of the practice as an illegitimate interference in the natural course of reproduction, on the other. The article tries to show that at least in the well defined context of sex selection by PGD, when IVF was performed for independent medical reasons, there is no danger to either the child or the mother and hence that the practice should be permitted. Furthermore, the alleged dangers to society are demonstrated to be mostly illusory. On the one hand, the demographic danger is usually overstated and lacks historical support. On the other hand, the feminist claim that sex selection is necessarily discriminatory is found to be both theoretically and empirically groundless. The article's conclusion is that despite widespread intuitive objection to the practice of sex selection, it can be justified in terms of parental autonomy and falls within the value of family planning. This liberal view does not, however, imply that having a child of the desired sex is the parents' right, nor does it apply to sex selection in later phases of gestation (abortions and obviously, infanticide).


Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation.
Snail1 is a central regulator of epithelial cell adhesion and movement in epithelial-to-mesenchymal transitions (EMTs) during embryo development; a process reactivated during cancer metastasis. While induction of Snail1 transcription precedes EMT induction, post-translational regulation of Snail1 is also critical for determining Snail1's protein level, subcellular localization, and capacity to induce EMT. To identify novel post-translational regulators of Snail1, we developed a live cell, bioluminescence-based screen. From a human kinome RNAi screen, we have identified Lats2 kinase as a novel regulator of Snail1 protein level, subcellular localization, and thus, activity. We show that Lats2 interacts with Snail1 and directly phosphorylates Snail1 at residue T203. This occurs in the nucleus and serves to retain Snail1 in the nucleus thereby enhancing its stability. Lats2 was found to positively influence cellular EMT and tumour cell invasion, in a Snail1-dependent manner. Indeed during TGFβ-induced EMT Lats2 is activated and Snail1 phosphorylated at T203. Analysis in mouse and zebrafish embryo development confirms that Lats2 acts as a positive modulator of Snail1 protein level and potentiates its in vivo EMT activity.


Knowing but not doing: selecting priority conservation areas and the research-implementation gap.
Conservation assessment is a rapidly evolving discipline whose stated goal is the design of networks of protected areas that represent and ensure the persistence of nature (i.e., species, habitats, and environmental processes) by separating priority areas from the activities that degrade or destroy them. Nevertheless, despite a burgeoning scientific literature that ever refines these techniques for allocating conservation resources, it is widely believed that conservation assessments are rarely translated into actions that actually conserve nature. We reviewed the conservation assessment literature in peer-reviewed journals and conducted survey questionnaires of the authors of these studies. Two-thirds of conservation assessments published in the peer-reviewed scientific literature do not deliver conservation action, primarily because most researchers never plan for implementation. This research-implementation gap between conservation science and real-world action is a genuine phenomenon and is a specific example of the "knowing-doing gap" that is widely recognized in management science. Given the woefully inadequate resources allocated for conservation, our findings raise questions over the utility of conservation assessment science, as currently practiced, to provide useful, pragmatic solutions to conservation planning problems. A reevaluation of the conceptual and operational basis of conservation planning research is urgently required. We recommend the following actions for beginning a process for bridging the research-implementation gap in conservation planning: (1) acknowledge the research-implementation gap is real, (2) source research questions from practitioners, (3) situate research within a broader conservation planning model, (4) expand the social dimension of conservation assessments, (5) support conservation plans with transdisciplinary social learning institutions, (6) reward academics for societal engagement and implementation, and (7) train students in skills for "doing" conservation.


PET-based dose painting in non-small cell lung cancer: Comparing uniform dose escalation with boosting hypoxic and metabolically active sub-volumes.
We compared two imaging biomarkers for dose-escalation in patients with advanced non-small cell lung cancer (NSCLC). Treatment plans boosting metabolically active sub-volumes defined by FDG-PET or hypoxic sub-volumes defined by HX4-PET were compared with boosting the entire tumour. Ten NSCLC patients underwent FDG- and HX4-PET/CT scans prior to radiotherapy. Three isotoxic dose-escalation plans were compared per patient: plan A, boosting the primary tumour (PTVprim); plan B, boosting sub-volume with FDG >50% SUVmax (PTVFDG); plan C, boosting hypoxic volume with HX4 tumour-to-background >1.4 (PTVHX4). Average boost volumes were 507 ± 466 cm(3) for PTVprim, 173 ± 127 cm(3) for PTVFDG and 114 ± 73 cm(3) for PTVHX4. The smaller PTVHX4 overlapped on average 87 ± 16% with PTVFDG. Prescribed dose was escalated to 87 ± 10 Gy for PTVprim, 107 ± 20 Gy for PTVFDG, and 117 ± 15 Gy for PTVHX4, with comparable doses to the relevant organs-at-risk (OAR). Treatment plans are available online (https://www.cancerdata.org/10.1016/j.radonc.2015.07.013). Dose escalation based on metabolic sub-volumes, hypoxic sub-volumes and the entire tumour is feasible. Highest dose was achieved for hypoxia plans, without increasing dose to OAR. For most patients, boosting the metabolic sub-volume also resulted in boosting the hypoxic volume, although to a lower dose, but not vice versa.


Time-resolved Hadamard fluorescence imaging.
We present a new concept for fluorescence lifetime imaging (FLIM) based on time-resolved Hadamard imaging (HI). HI allows image acquisition by use of one single-point detector without requiring a moving scanning stage. Moreover, it reduces the influence of detector noise compared with raster scanning. By use of Monte Carlo simulations it could be confirmed that Hadamard transformation may decrease the error in lifetime estimation and in general in fluorescence parameter estimation when the signal-to-noise ratio is low and detector dark noise is high. This concept may find applications whenever the performance of FLIM or similar methods is limited by high dark-count rates and when the use of a single-point detector is preferable.


Biomarkers of kidney injury.
Acute kidney injury (AKI) represents a common serious clinical problem. Up to date mortality due to AKI, especially in intensive care units, has not been changed significantly over the past 50 years. This is partly due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to recognition of the early period of AKI. Our objective was to review established markers versus novel urine and serum biomarkers of AKI in humans, which have progressed to clinical phase with regard to their diagnostic and prognostic value. A review was performed on the basis of literature search of renal failure, acute kidney injury, and biomarkers in Pubmed. Next to established biomarkers as creatinine and cystatin C, other molecules such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic peptide (MCP-1), Netrin-1, and interleukin (IL)-18 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. In clinical settings with incipient AKI, not only the development and the implementation of more sensitive biomarkers are required for earlier treatment initiation in order to attenuate the severity of kidney injury, but also equally important remains the substantial improvement and application of refined and prophylactic therapeutic options in these situations. Adequately powered clinical trials testing a row of biomarkers are warranted before they may qualify for full adoption in clinical practice.


Eye movement desensitization and reprocessing for posttraumatic stress disorder: a pilot blinded, randomized study of stimulation type.
Eye movement desensitization and reprocessing (EMDR) is becoming a recognized and accepted form of psychotherapy for posttraumatic stress disorder (PTSD). Yet, its mechanism of action remains unclear and much controversy exists about whether eye movements or other forms of bilateral kinesthetic stimulation contribute to its clinical effects beyond the exposure elements of the procedure. Twenty-one patients with single-event PTSD (average Impact of Event Scale score: 49.5) received three consecutive sessions of EMDR with three different types of auditory and kinesthetic stimulation (tones and vibrations): intermittent alternating right-left (as commonly used with the standard EMDR protocol), intermittent simultaneous bilateral, and continuous bilateral. Therapists were blinded to the type of stimulation they delivered, and stimulation type assignment was randomized and counterbalanced. All three stimulation types resulted in clinically significant reductions of subjective units of distress (SUD). Yet, alternating stimulation resulted in faster reductions of SUD when only sessions starting with a new target memory were considered. There are clinically significant effects of the EMDR procedure that appear to be independent of the nature of the kinesthetic stimulation used. However, alternating stimulation may confer an additional benefit to the EMDR procedure that deserves attention in future studies.


The adaptive nature of culture. A cross-cultural analysis of the returns of local environmental knowledge in three indigenous societies.
Researchers have argued that the behavioral adaptations that explain the success of our species are partially cultural, i.e., cumulative and socially transmitted. Thus, understanding the adaptive nature of culture is crucial to understand human evolution. We use a cross-cultural framework and empirical data purposely collected to test whether culturally transmitted and individually appropriated knowledge provides individual returns in terms of hunting yields and health and, by extension, to nutritional status, a proxy for individual adaptive success. Data were collected in three subsistence-oriented societies: the Tsimane' (Amazon), the Baka (Congo Basin), and the Punan (Borneo). Results suggest that variations in individual levels of local environmental knowledge relate to individual hunting returns and to self-reported health, but not to nutritional status. We argue that this paradox can be explained through the prevalence of sharing: individuals achieving higher returns to their knowledge transfer them to the rest of the population, which explains the lack of association between knowledge and nutritional status. The finding is in consonance with previous research highlighting the importance of cultural traits favoring group success, but pushes it forward by elucidating the mechanisms through which individual and group level adaptive forces interact.


Molecular targets for antiepileptic drug development.
This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the alpha subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, alpha2-delta voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABA(A) receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA(B) and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABA(A) receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.


Identification of the human and rat P450 enzymes responsible for the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-ME). The terminal step in the bioactivation of disulfiram.
The present study investigated the role of rat and human cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-Me) to S-methyl N,N-diathylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the putative active metabolite of disulfiram. DETC-Me sulfoxidation by microsomes from male and female rats treated with various cytochrome P450-enzyme inducers suggested that multiple enzymes can catalyze this reaction, and these include, CYP1A1/2, CYP2B1/2, and CYP3A1/2. All cDNA-expressed human cytochrome P450 enzymes examined catalyzed the sulfoxidation of DETC-Me. The turnover rates (min-1) of DETC-Me sulfoxidation by the cDNA-expressed cytochrome P450 enzymes ranked as follows: CYP3A4 > CYP2A6 = CYP2C9 > CYP1A2 > CYP2B6 = CYP2E1 > CYP1A1 > CYP2D6. Interestingly, CYP3A4 ranked first or last, depending on whether or not additional NADPH-cytochrome P450 reductase was coexpressed in the lymphoblastoid cells. This complicated estimates of the contribution of CYP3A4 to DETC-Me sulfoxidation by human liver microsomes. The sample-to-sample variation in DETC-Me sulfoxidation by bank of human liver microsomes (N=13) correlated highly with coumarin 7-hydroxylation (r=0.88) and testosterone 6beta-hydroxylation (r=0.90), suggesting that CYP2A6 and CYP3A4/5 contribute to the sulfoxidation of DETC-Me by human liver microsomes. Although, chlorzoxazone 6-hydroxylation (a marker for CYP2E1) correlated poorly with DETC-Me sulfoxidation, the correlation improved from r=0.07 to r=0.44 when DETC-Me sulfoxidation was studied in the presence of the CYP2A6 inhibitor, coumarin. Similarly, when DETC-Me sulfoxidation was studied in the presence of diethyldithiocarbamate (DDTC), the inhibited DETC-Me sulfoxidase activity correlated better (r=0.50) with chlorzoxazone 6-hydroxylase, compared with DETC-Me sulfoxidase activity in the absence of DDTC (r=0.09). Polyclonal antibodies against CYP2E1 caused a modest inhibition (30%) of DETC-Me sulfoxidation by human liver microsomes. Anti-CYP3A1 antibodies completely inhibited DETC-Me sulfoxidation by cDNA-expressed CYP3A4. Under similar conditions, DETC-Me sulfoxidation by human liver microsomes was only partially inhibited by anti-CYP3A1 antibodies. Although studies with the rat and cDNA-expressed cytochrome P450 enzymes suggested that CYP1A2 contributed to DETC-Me sulfoxidation, this reaction was not inhibited by either furafylline ( a mechanism-based inhibitor of CYP1A2) or antibodies against CYP1A1/2. A significant role for CYP2C9 was excluded by the inability of sulfaphenazole to inhibit the sulfoxidation of DETC-Me by human liver microsomes. Collectively, these data suggest that multiple cytochrome P450 enzymes can catalyze the sulfoxidation of DETC-Me. In human liver microsomes the CYP2A6, CYP2E1, and CYP3A4/5 all contribute significantly to the sulfoxidation of DETC-Me. It is interesting to note that DDTC, the reduced metabolite of disulfiram, is known to inhibit these same enzymes. The ability of DDTC to block the formation of DETC-Me sulfoxide may explain why the dose of disulfiram required to produce a disulfiram-ethanol reaction in alcoholics is so variable and often inadequate.


Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps.
Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.


Application of pressure scanning to the tuning of a high resolution dye laser.
Advantages of pressure scanning over other methods of tuning the wavelength of dye lasers are discussed. The construction of a pressure scanned high resolution dye laser is described. The laser has a scan range of more than 40 cm(-1) in its intermediate resolution mode, an improvement on the order of a hundredfold over previous methods of tuning. Preliminary tests have indicated a scan range of 4 cm(-1) in the high resolution mode. As a demonstration of its applicability and versatility, the laser was used to xesolve the ground state splitting of the chromium isotopes in ruby.


Reducing childhood obesity through U.S. federal policy: a microsimulation analysis.
Childhood obesity prevalence remains high in the U.S., especially among racial/ethnic minorities and low-income populations. Federal policy is important in improving public health given its broad reach. Information is needed about federal policies that could reduce childhood obesity rates and by how much. To estimate the impact of three federal policies on childhood obesity prevalence in 2032, after 20 years of implementation. Criteria were used to select the three following policies to reduce childhood obesity from 26 recommended policies: afterschool physical activity programs, a $0.01/ounce sugar-sweetened beverage (SSB) excise tax, and a ban on child-directed fast food TV advertising. For each policy, the literature was reviewed from January 2000 through July 2012 to find evidence of effectiveness and create average effect sizes. In 2012, a Markov microsimulation model estimated each policy's impact on diet or physical activity, and then BMI, in a simulated school-aged population in 2032. The microsimulation predicted that afterschool physical activity programs would reduce obesity the most among children aged 6-12 years (1.8 percentage points) and the advertising ban would reduce obesity the least (0.9 percentage points). The SSB excise tax would reduce obesity the most among adolescents aged 13-18 years (2.4 percentage points). All three policies would reduce obesity more among blacks and Hispanics than whites, with the SSB excise tax reducing obesity disparities the most. All three policies would reduce childhood obesity prevalence by 2032. However, a national $0.01/ounce SSB excise tax is the best option.


Variations on fibrinogen-erythrocyte interactions during cell aging.
Erythrocyte hyperaggregation, a cardiovascular risk factor, is considered to be caused by an increase in plasma adhesion proteins, particularly fibrinogen. We have recently reported a specific binding between fibrinogen and an erythrocyte integrin receptor with a β(3) or β(3)-like subunit. In this study we evaluate the influence of erythrocyte aging on the fibrinogen binding. By atomic force microscopy-based force spectroscopy measurements we found that increasing erythrocyte age, there is a decrease of the binding to fibrinogen by decreasing the frequency of its occurrence but not its force. This observation is reinforced by zeta-potential and fluorescence spectroscopy measurements. We conclude that upon erythrocyte aging the number of fibrinogen molecules bound to each cell decreases significantly, due to the progressive impairment of the specific fibrinogen-erythrocyte receptor interaction. Knowing that younger erythrocytes bind more to fibrinogen, we could presume that this population is the main contributor to the cardiovascular diseases associated with increased fibrinogen content in blood, which could disturb the blood flow. Our data also show that the sialic acids exposed on the erythrocyte membrane contribute for the interaction with fibrinogen, possibly by facilitating its binding to the erythrocyte membrane receptor.


Two-phase importance sampling for inference about transmission trees.
There has been growing interest in the statistics community to develop methods for inferring transmission pathways of infectious pathogens from molecular sequence data. For many datasets, the computational challenge lies in the huge dimension of the missing data. Here, we introduce an importance sampling scheme in which the transmission trees and phylogenies of pathogens are both sampled from reasonable importance distributions, alleviating the inference. Using this approach, arbitrary models of transmission could be considered, contrary to many earlier proposed methods. We illustrate the scheme by analysing transmissions of Streptococcus pneumoniae from household to household within a refugee camp, using data in which only a fraction of hosts is observed, but which is still rich enough to unravel the within-household transmission dynamics and pairs of households between whom transmission is plausible. We observe that while probability of direct transmission is low even for the most prominent cases of transmission, still those pairs of households are geographically much closer to each other than expected under random proximity.


Heart rate variability and sustained attention in ADHD children.
The major goal of the current study was to investigate the association between continuous performance tests (CPTs) and the heart rate variability (HRV) of attention deficit hyperactivity disorder (ADHD) children. The HRV, specifically the 0.10-Hz component, may be considered to be a psychophysiological index of effort allocation (motivation): The less effort the subject allocates, the greater the 0.10-Hz component. Results indicated that, compared to controls, ADHD subjects had a greater 0.10-Hz component, which was associated with poor test performance over time. Thus, using a psychophysiological measure, we were able to confirm the clinical concept of ADHD from a motivational perspective.


Tracing the molecular basis of transcriptional dynamics in noisy data by using an experiment-based mathematical model.
Changes in transcription factor levels, epigenetic status, splicing kinetics and mRNA degradation can each contribute to changes in the mRNA dynamics of a gene. We present a novel method to identify which of these processes is changed in cells in response to external signals or as a result of a diseased state. The method employs a mathematical model, for which the kinetics of gene regulation, splicing, elongation and mRNA degradation were estimated from experimental data of transcriptional dynamics. The time-dependent dynamics of several species of adipose differentiation-related protein (ADRP) mRNA were measured in response to ligand activation of the transcription factor peroxisome proliferator-activated receptor δ (PPARδ). We validated the method by monitoring the mRNA dynamics upon gene activation in the presence of a splicing inhibitor. Our mathematical model correctly identifies splicing as the inhibitor target, despite the noise in the data.


Enhanced photovoltaic performance of ultrathin Si solar cells via semiconductor nanocrystal sensitization: energy transfer vs. optical coupling effects.
Excitonic energy transfer (ET) offers exciting opportunities for advances in optoelectronic devices such as solar cells. While recent experimental attempts have demonstrated its potential in both organic and inorganic photovoltaics (PVs), what remains to be addressed is quantitative understanding of how different ET modes contribute to PV performance and how ET contribution is differentiated from the classical optical coupling (OC) effects. In this study, we implement an ET scheme using a PV device platform, comprising CdSe/ZnS nanocrystal energy donor and 500 nm-thick ultrathin Si acceptor layers, and present the quantitative mechanistic description of how different ET modes, distinguished from the OC effects, increase the light absorption and PV efficiency. We find that nanocrystal sensitization enhances the short circuit current of ultrathin Si solar cells by up to 35%, of which the efficient ET, primarily driven by a long-range radiative mode, contributes to 38% of the total current enhancement. These results not only confirm the positive impact of ET but also provide a guideline for rationally combining the ET and OC effects for improved light harvesting in PV and other optoelectronic devices.


Increased serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in obesity and fatty liver.
Leukocyte cell-derived chemotaxin 2 (LECT2) is a signaling molecule expressed in the liver and regulated by Wnt/β-catenin pathways implicated in hepatic metabolism. However, the clinical relevance of LECT2 in obesity and fatty liver is unknown. The objective of this study was to determine whether serum LECT2 levels are affected by of obesity and fatty liver. A cross sectional study comprising 231 Japanese adult subjects were tested for LECT2 using a highly sensitive assay. We evaluated the associations between LECT2 and the anthropometric or clinical markers of obesity and fatty liver. The mean serum LECT2 levels were 43.5 ± 13.6 ng/mL. LECT2 positively correlated with all the anthropometric measures of obesity: body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio (W/Ht). Multiple regression analysis revealed that LECT2 is independently related to γ-glutamyl transpeptidase (γ-GTP), triglyceride, and age in males, whereas in females it was related to the homeostasis model assessment ratio, blood urea nitrogen, high-density lipoprotein cholesterol, and γ-GTP. Receiver operating characteristics curve analyses revealed that LECT2 correlated with obesity [area under the curve (AUC) 0.655, 95% confidence interval (CI) = 0.551-0.758, p = 0.002 in males; AUC 0.670, 95% CI = 0.570-0.770, p < 0.001 in females] and fatty liver (AUC 0.646, 95% CI = 0.544-0.749, p = 0.004 in males; AUC 0.733, 95% CI = 0.621-0.844, p < 0.001 in females). The present study indicates that serum LECT2 levels are increased by obesity and fatty liver, and suggests that LECT2 is a novel obesity-related protein.


Personalised normative feedback for preventing alcohol misuse in university students: Solomon three-group randomised controlled trial.
Young people tend to over-estimate peer group drinking levels. Personalised normative feedback (PNF) aims to correct this misperception by providing information about personal drinking levels and patterns compared with norms in similar aged peer groups. PNF is intended to raise motivation for behaviour change and has been highlighted for alcohol misuse prevention by the British Government Behavioural Insight Team. The objective of the trial was to assess the effectiveness of PNF with college students for the prevention of alcohol misuse. Solomon three-group randomised controlled trial. 1751 students, from 22 British Universities, allocated to a PNF group, a normal control group, or a delayed measurement control group to allow assessment of any measurement effects. PNF was provided by email. Participants completed online questionnaires at baseline, 6- and 12-months (only 12-months for the delayed measurement controls). Drinking behaviour measures were (i) alcohol disorders; (ii) frequency; (iii) typical quantity, (iv) weekly consumption; (v) alcohol-related problems; (vi) perceived drinking norms; and (vii) positive alcohol expectancies. Analyses focused on high-risk drinkers, as well as all students, because of research evidence for the prevention paradox in student drinkers. Follow-up rates were low, with only 50% and 40% responding at 6- and 12-months, respectively, though comparable to similar European studies. We found no evidence for any systematic attrition bias. Overall, statistical analyses with the high risk sub-sample, and for all students, showed no significant effects of the intervention, at either time-point, in a completed case analysis and a multiple imputation analysis. We found no evidence for the effectiveness of PNF for the prevention of alcohol misuse and alcohol-related problems in a UK student population. Controlled-Trials.com ISRCTN30784467.


Modification of high-heeled shoes to decrease pronation during gait.
One of the reasons that high heels may contribute to the formation of halux valgus is that the wearers pronate during propulsion. This pilot study was performed to determine whether relocation of the heel under the counter of a fashion high-heeled pump could change the degree of pronation of the foot during the gait cycle. The authors report that more foot stability was experienced by the subjects when the center of the heel was offset between 2 and 4 mm medial to the center of the heel counter. This study is designed to promote further research into whether the shoe industry should change the design parameters of high-heeled fashion shoes in order to improve foot function.


Effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease: a 3-year follow-up study.
Pompe disease is a storage disorder characterized by deficient or absent activity of the enzyme acid alpha-glucosidase. As a result of ineffective metabolism, glycogen accumulates in muscle tissues. Patients with a classic infantile-onset form present by the first few months of life with hypertrophic cardiomyopathy and muscle weakness. If left untreated, these patients rapidly die of cardiorespiratory failure. A cross-reactive immunological material (CRIM)-negative status is predictive of high anti-alglucosidase alpha antibody titers. However, CRIM-positive patients also sometimes develop robust antibody titers. High antibody titers complicate therapeutic management, and those patients have a worse clinical outcome of enzyme replacement therapy (ERT).Four years ago, we successfully used an immune modulation therapy (IMT) protocol in a CRIM-positive infantile-onset patient with Pompe disease in whom ERT had to be discontinued because of severe infusion-associated reactions. She was found to be positive for anti-alglucosidase alpha antibodies. IMT (rituximab, methotrexate, and intravenous gammaglobulin) was started, and ERT was safely reintroduced during the IMT induction phase without any complications. Antibodies disappeared; IMT was tapered and discontinued; and cardiomyopathy steadily improved. During more than 3 years of follow-up, she remained ventilator dependent, and no gains in motor skills were noticed. The antibodies are still undetectable, and no adverse reactions associated with IMT had occurred. The cardiomyopathy is gradually increasing, but there is still ~ 50 % reduction as compared with the highest value measured. Although the reversal of clinical decline in our CRIM-positive and antibody-positive infant cannot be solely attributed to IMT, this protocol proved itself efficient and safe.


Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo.
Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperones in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53TαS Tg mouse model and the adeno-associated virus-transduced rat model of A53TαS-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies.


The genetic prehistory of southern Africa.
Southern and eastern African populations that speak non-Bantu languages with click consonants are known to harbour some of the most ancient genetic lineages in humans, but their relationships are poorly understood. Here, we report data from 23 populations analysed at over half a million single-nucleotide polymorphisms, using a genome-wide array designed for studying human history. The southern African Khoisan fall into two genetic groups, loosely corresponding to the northwestern and southeastern Kalahari, which we show separated within the last 30,000 years. We find that all individuals derive at least a few percent of their genomes from admixture with non-Khoisan populations that began ∼1,200 years ago. In addition, the East African Hadza and Sandawe derive a fraction of their ancestry from admixture with a population related to the Khoisan, supporting the hypothesis of an ancient link between southern and eastern Africa.


Molecular level insight into intra-solvent interaction effects on protein stability and aggregation.
Protein based therapeutics hold great promise in the treatment of human diseases and disorders and subsequently, they have become the fastest growing sector of new drugs being developed. Proteins are, however, inherently unstable and the degraded form can be quite harmful if administered to a patient. Of the various degradation pathways, aggregation is one of the most common and a cause for great concern. Aggregation suppressing additives have long been used to stabilize proteins, and they still remain the most viable option for combating this problem. Much work has been devoted toward investigating the behavior of commonly used additives and the resulting models give valuable insight toward explaining aggregation suppression. In a few cases, an explanation for unique behavior is lacking or new insight provides an alternate explanation. Additive selection and the development of better performing additives may benefit from a more refined understanding of how commonly used additives inhibit or enhance aggregation. In this review, we focus on recent molecular-level studies into how a select group of commonly used additives interact with proteins and subsequently influence aggregation. The intent of the review is not meant to be comprehensive for each additive but rather to provide new insights into additive-additive interactions, which may be contributing to protein-additive interactions. This is something that is often overlooked but yet essential to understanding the effect of additives on aggregation. The importance of understanding such interactions is clear when one considers that most formulations contain a mixture of cosolutes and that ideal stability might be better achieved through tuning intra-solvent interactions. We give an example of this when we describe how novel aggregation suppressing additives were developed from the knowledge gained from the reviewed studies.


Genome-wide analysis of WOX genes in upland cotton and their expression pattern under different stresses.
WUSCHEL-related homeobox (WOX) family members play significant roles in plant growth and development, such as in embryo patterning, stem-cell maintenance, and lateral organ formation. The recently published cotton genome sequences allow us to perform comprehensive genome-wide analysis and characterization of WOX genes in cotton. In this study, we identified 21, 20, and 38 WOX genes in Gossypium arboreum (2n = 26, A2), G. raimondii (2n = 26, D5), and G. hirsutum (2n = 4x = 52, (AD)t), respectively. Sequence logos showed that homeobox domains were significantly conserved among the WOX genes in cotton, Arabidopsis, and rice. A total of 168 genes from three typical monocots and six dicots were naturally divided into three clades, which were further classified into nine sub-clades. A good collinearity was observed in the synteny analysis of the orthologs from At and Dt (t represents tetraploid) sub-genomes. Whole genome duplication (WGD) and segmental duplication within At and Dt sub-genomes played significant roles in the expansion of WOX genes, and segmental duplication mainly generated the WUS clade. Copia and Gypsy were the two major types of transposable elements distributed upstream or downstream of WOX genes. Furthermore, through comparison, we found that the exon/intron pattern was highly conserved between Arabidopsis and cotton, and the homeobox domain loci were also conserved between them. In addition, the expression pattern in different tissues indicated that the duplicated genes in cotton might have acquired new functions as a result of sub-functionalization or neo-functionalization. The expression pattern of WOX genes under different stress treatments showed that the different genes were induced by different stresses. In present work, WOX genes, classified into three clades, were identified in the upland cotton genome. Whole genome and segmental duplication were determined to be the two major impetuses for the expansion of gene numbers during the evolution. Moreover, the expression patterns suggested that the duplicated genes might have experienced a functional divergence. Together, these results shed light on the evolution of the WOX gene family, and would be helpful in future research.


Retrospective analysis of in vivo recovery and clearance during continuous infusion of recombinant factor VIII products: a single-institution study.
Continuous infusion (CI) of recombinant FVIII (rFVIII) concentrates has been reported as an effective and safe method to achieve haemostasis during major surgeries or severe bleeding events. For more effective and safer CI, better understanding of in vivo recovery (IVR) and clearance (CL) issues is imperative. We investigated the following factors affecting IVR and CL using univariate and multivariate regression analyses during 47 CIs in 34 patients: rFVIII concentrate type, haemophilia severity, blood type, the presence of hepatitis C virus (HCV) or human immunodeficiency virus (HIV), age and body mass index (BMI). The mean IVR was 1.64 ± 0.49 IU dL-1 per IU kg-1 , and the mean CL during CI was 3.56 ± 1.57 mL h-1 kg-1 . The univariate and multivariate regression analyses showed that the CL of octocog alfa was significantly lower than that of rurioctocog alfa (P = 0.043 and 0.0034, respectively). There was a significant difference in BMI in the univariate and multivariate regression analyses (P = 0.0403 and 0.0376, respectively). This study indicated that CL during CI was potentially affected by the type of rFVIII concentrate used and BMI.


Using administrative data to look at changes in the level and distribution of out-of-pocket medical expenditure: An example using Medicare data from Australia.
Australia's universal health insurance system Medicare generates very large amounts of data on out-of-pocket expenditure (OOPE), but only highly aggregated statistics are routinely published. Our primary purpose is to develop indices from the Medicare administrative data to quantify changes in the level and distribution of OOPE on out-of-hospital medical services over time. Data were obtained from the Australian Hypertension and Absolute Risk Study, which involved patients aged 55 years and over (n=2653). Socio-economic and clinical information was collected and linked to Medicare records over a five-year period from March 2008. The Fisher price and quantity indices were used to evaluate year-to-year changes in OOPE. The relative concentration index was used to evaluate the distribution of OOPE across socio-economic strata. Our price index indicates that overall OOPE were not rising faster than inflation, but there was considerable variation across different types of services (e.g. OOPE on professional attendances rose by 20% over a five-year period, while all other items fell by around 14%). Concentration indices, adjusted for demographic factors and clinical need, indicate that OOPE tends to be higher among those on higher incomes. A major challenge in utilizing large administrative data sets is to develop reliable and easily interpretable statistics for policy makers. Price, quantity and concentration indices represent statistics that move us beyond the average.


Maximal exercise testing variables and 10-year survival: fitness risk score derivation from the FIT Project.
To determine which routinely collected exercise test variables most strongly correlate with survival and to derive a fitness risk score that can be used to predict 10-year survival. This was a retrospective cohort study of 58,020 adults aged 18 to 96 years who were free of established heart disease and were referred for an exercise stress test from January 1, 1991, through May 31, 2009. Demographic, clinical, exercise, and mortality data were collected on all patients as part of the Henry Ford ExercIse Testing (FIT) Project. Cox proportional hazards models were used to identify exercise test variables most predictive of survival. A "FIT Treadmill Score" was then derived from the β coefficients of the model with the highest survival discrimination. The median age of the 58,020 participants was 53 years (interquartile range, 45-62 years), and 28,201 (49%) were female. Over a median of 10 years (interquartile range, 8-14 years), 6456 patients (11%) died. After age and sex, peak metabolic equivalents of task and percentage of maximum predicted heart rate achieved were most highly predictive of survival (P<.001). Subsequent addition of baseline blood pressure and heart rate, change in vital signs, double product, and risk factor data did not further improve survival discrimination. The FIT Treadmill Score, calculated as [percentage of maximum predicted heart rate + 12(metabolic equivalents of task) - 4(age) + 43 if female], ranged from -200 to 200 across the cohort, was near normally distributed, and was found to be highly predictive of 10-year survival (Harrell C statistic, 0.811). The FIT Treadmill Score is easily attainable from any standard exercise test and translates basic treadmill performance measures into a fitness-related mortality risk score. The FIT Treadmill Score should be validated in external populations.


Complete Genome Sequence of Cupriavidus basilensis 4G11, Isolated from the Oak Ridge Field Research Center Site.
Cupriavidus basilensis 4G11 was isolated from groundwater at the Oak Ridge Field Research Center (FRC) site. Here, we report the complete genome sequence and annotation of Cupriavidus basilensis 4G11. The genome contains 8,421,483 bp, 7,661 predicted protein-coding genes, and a total GC content of 64.4%.


Moclobemide and cognitive behavioral therapy in the treatment of social phobia. A six-month controlled study and 24 months follow up.
The aim of the study was to assess the 6-months treatment efficacy and 24-month follow up of three different therapeutic programs (A. moclobemide and supportive guidance, B. group cognitive-behavioral therapy and pill placebo, and C. combination of moclobemide and group cognitive-behavioral therapy) in patients with a generalized form of social phobia. Eighty one patients (38 males and 43 females) were randomly assigned to three different therapeutic programs. Patients were regularly assessed on a monthly basis by an independent rater on the LSAS (Liebowitz Social Anxiety scale), CGI (Clinical Global Impression) for severity and change and BAI (Beck Anxiety Inventory). Altogether, sixty-six patients completed the six month treatment period and 15 patients dropped out. All therapeutic groups showed significant improvement. A combination of CBT and pharmacotherapy yielded the most rapid effect. Moclobemide was superior for the reduction of the subjective general anxiety (BAI) during the first 3 months of treatment, but its influence on avoidant behavior (LSAS avoidance subscale) was less pronounced. Conversely, CBT was the best choice for reduction of avoidant behavior while a reduction of subjective general anxiety appeared later than in moclobemide. After 6 months of treatment there were best results reached in groups treated with CBT and there was no advantage of the combined treatment. The relapse rate during the 24-month follow up was significantly lower in the group treated with CBT in comparison with the group A. formerly treated with moclobemide alone.