Activation of muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex.
There is strong evidence that decrements in neuronal activation in perirhinal cortex when a novel stimulus is repeated provide a neural substrate of visual recognition memory. There is also strong evidence that muscarinic acetylcholine (ACh) receptors are involved in learning and memory. However, the mechanisms underlying neuronal decrements in the perirhinal cortex and the basis of ACh involvement in learning and memory are not understood. In an in vitro preparation of rat perirhinal cortex we now demonstrate that activation of ACh receptors by carbachol (CCh) produces long-lasting depression (LLD) of synaptic transmission that is dependent on muscarinic M1 receptor activation. Crucially, the induction of this form of LLD requires neither N-methyl-D-aspartate receptor activation nor synaptic stimulation. CCh-induced LLD was not blocked by the protein kinase C inhibitors staurosporine or BIM, or by the protein phosphatase inhibitor okadaic acid. However, each of cyclopiazonic acid (an agent that depletes intracellular calcium stores) and anisomycin (an inhibitor of protein synthesis) significantly reduced the magnitude of CCh-induced LLD. These mechanisms triggered by muscarinic receptor activation could play a role in the induction and/or expression of certain forms of activity-dependent long-term depression in perirhinal cortex. An understanding of CCh-induced LLD may thus provide clues to the mechanisms underlying lasting neuronal decrements that occur in the perirhinal cortex and hence for neural substrates of visual recognition memory.


A peer education example on HIV/AIDS at a high school in Ankara.
Adolescence is a transition period between childhood and adulthood in which physical, sexual and psychosocial changes occur. Sexually Transmitted Infections (STI) are the most common reproductive health problems adolescents face. Peer education is a very useful method in adolescents' education, especially on risk factors and risk taking behaviors. This peer education intervention study, including two base line studies (one before and one after the intervention), was conducted in four classes of an Anatolian high school in Ankara in 2000. The aim of the study was to evaluate the success of the peer education model. There was a significant difference in the general scores of the students before (29.52; SD = 4.38) and after (31.89; SD = 4.96) education by peer educators (p = 0.000). This study might have assisted the study population in establishing safe sex practices for a healthy sexual future.


Evolutionary and transmission dynamics of reassortant H5N1 influenza virus in Indonesia.
H5N1 highly pathogenic avian influenza (HPAI) viruses have seriously affected the Asian poultry industry since their recurrence in 2003. The viruses pose a threat of emergence of a global pandemic influenza through point mutation or reassortment leading to a strain that can effectively transmit among humans. In this study, we present phylogenetic evidences for the interlineage reassortment among H5N1 HPAI viruses isolated from humans, cats, and birds in Indonesia, and identify the potential genetic parents of the reassorted genome segments. Parsimony analyses of viral phylogeography suggest that the reassortant viruses may have originated from greater Jakarta and surroundings, and subsequently spread to other regions in the West Java province. In addition, Bayesian methods were used to elucidate the genetic diversity dynamics of the reassortant strain and one of its genetic parents, which revealed a more rapid initial growth of genetic diversity in the reassortant viruses relative to their genetic parent. These results demonstrate that interlineage exchange of genetic information may play a pivotal role in determining viral genetic diversity in a focal population. Moreover, our study also revealed significantly stronger diversifying selection on the M1 and PB2 genes in the lineages preceding and subsequent to the emergence of the reassortant viruses, respectively. We discuss how the corresponding mutations might drive the adaptation and onward transmission of the newly formed reassortant viruses.


Surface characterization of SLActive dental implants.
The aim of the study was to characterize the surface chemistry, hydration capacity, topography and roughness of the root part of a hydrophilic sandblasted and acid-etched titanium dental implant (SLActive). Implants as received (SAR), after water rinsing (SAW) and after ultrasonication in water (SAU) were subjected to x-ray photoelectron spectroscopy (XPS) elemental and binding state analysis. Scanning electron microscopy plus energy dispersive x-ray microanalysis (SEM/EDX), reflection Fourier transform infrared microspectroscopy (RFTIRM) and hydration/ dehydration cycling by environmental scanning electron microscopy (ESEM), were performed in SAR, whereas SAU implants were subjected to 3D-optical profilometry and SEM. For all the experiments, a conventional sandblasted and acid-etched implant (SLA ) of the same manufacturer was used as control. XPS showed lower mean C content in SAR than SLA, but not significantly different. In SAW, the C and O contents were increased. Significantly reduced C and increased Ti and O contents were found in SAU. Residual Na phases, other than NaCl, were traced in all SLActive groups. SAR demonstrated higher [-OH]/O2- ratio than SLA . EDX documented higher O, Na, Cl and lower Ti content in SAR. More -OH contributions were probed on SAR in comparison with SLA by RFTI RM. Ti-O peaks assigned to anatase, rutile and amorphous phases were found in both implant groups. The ESEM study revealed a full rehydration capacity in SAR, in contrast to SLA. No differences were found in the topography of SAU and SLA implant surfaces under the SEM. However, significantly greater values in spatial and functional roughness parameters were encountered in SAU. The increased surface hydroxylated titanium content and the greater spatial and functional roughness parameters, may explain the enhanced biological activity documented for SLActive in comparison with SLA.


ΔFosB induction correlates inversely with CB₁ receptor desensitization in a brain region-dependent manner following repeated Δ⁹-THC administration.
Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.


The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.
The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. The N-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and N- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long-term palliation or cure of melanoma.


Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells.
Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies.


A cardiovascular disease policy model that predicts life expectancy taking into account socioeconomic deprivation.
A policy model is a model that can evaluate the effectiveness and cost-effectiveness of interventions and inform policy decisions. In this study, we introduce a cardiovascular disease (CVD) policy model which can be used to model remaining life expectancy including a measure of socioeconomic deprivation as an independent risk factor for CVD. A state transition model was developed using the Scottish Heart Health Extended Cohort (SHHEC) linked to Scottish morbidity and death records. Individuals start in a CVD-free state and can transit to three CVD event states plus a non-CVD death state. Individuals who have a non-fatal first event are then followed up until death. Taking a competing risk approach, the cause-specific hazards of a first event are modelled using parametric survival analysis. Survival following a first non-fatal event is also modelled parametrically. We assessed discrimination, validation and calibration of our model. Our model achieved a good level of discrimination in each component (c-statistics for men (women)-non-fatal coronary heart disease (CHD): 0.70 (0.74), non-fatal cerebrovascular disease (CBVD): 0.73 (0.76), fatal CVD: 0.77 (0.80), fatal non-CVD: 0.74 (0.72), survival after non-fatal CHD: 0.68 (0.67) and survival after non-fatal CBVD: 0.65 (0.66)). In general, our model predictions were comparable with observed event rates for a Scottish randomised statin trial population which has an overlapping follow-up period with SHHEC. After applying a calibration factor, our predictions of life expectancy closely match those published in recent national life tables. Our model can be used to estimate the impact of primary prevention interventions on life expectancy and can assess the impact of interventions on inequalities.


No health without mental health.
About 14% of the global burden of disease has been attributed to neuropsychiatric disorders, mostly due to the chronically disabling nature of depression and other common mental disorders, alcohol-use and substance-use disorders, and psychoses. Such estimates have drawn attention to the importance of mental disorders for public health. However, because they stress the separate contributions of mental and physical disorders to disability and mortality, they might have entrenched the alienation of mental health from mainstream efforts to improve health and reduce poverty. The burden of mental disorders is likely to have been underestimated because of inadequate appreciation of the connectedness between mental illness and other health conditions. Because these interactions are protean, there can be no health without mental health. Mental disorders increase risk for communicable and non-communicable diseases, and contribute to unintentional and intentional injury. Conversely, many health conditions increase the risk for mental disorder, and comorbidity complicates help-seeking, diagnosis, and treatment, and influences prognosis. Health services are not provided equitably to people with mental disorders, and the quality of care for both mental and physical health conditions for these people could be improved. We need to develop and evaluate psychosocial interventions that can be integrated into management of communicable and non-communicable diseases. Health-care systems should be strengthened to improve delivery of mental health care, by focusing on existing programmes and activities, such as those which address the prevention and treatment of HIV, tuberculosis, and malaria; gender-based violence; antenatal care; integrated management of childhood illnesses and child nutrition; and innovative management of chronic disease. An explicit mental health budget might need to be allocated for such activities. Mental health affects progress towards the achievement of several Millennium Development Goals, such as promotion of gender equality and empowerment of women, reduction of child mortality, improvement of maternal health, and reversal of the spread of HIV/AIDS. Mental health awareness needs to be integrated into all aspects of health and social policy, health-system planning, and delivery of primary and secondary general health care.


Increased spontaneous formation of micronuclei in cultured fibroblasts of first-degree relatives of familial melanoma patients.
The phenomenon of spontaneous increased micronuclei and enhanced UV-sensitivity, which is known for familial cutaneous malignant melanoma (CMM) patients, could be demonstrated again in fibroblasts of 17 familial CMM patients. In order to determine if close relatives of familial CMM patients show both a comparable spontaneous chromosomal instability and enhanced UV-sensitivity, cultured fibroblasts of 24 healthy, first-degree relatives of patients with familial malignant melanoma were investigated. The cytokinesis-block micronucleous technique was used to detect enhanced chromosomal instability. Fibroblasts of the investigated relatives showed a significantly increased spontaneous formation of micronuclei, in comparison to 19 healthy controls, but no enhanced UV-sensitivity was evident. We conclude that chromosomal instability might be a hereditary trait and a causative factor in developing familial malignant melanoma. This supports the concept of a genetic predisposition to familial CMM and may help to identify high-risk family members at a cytogenetic level in addition to the common clinicopathological traits.


Quantitative assays of epidermal growth factor receptor in human breast cancer: cut-off points of clinical relevance.
Epidermal growth factor receptor (EGFr) assays were performed by 3 different methods on 246 human primary breast carcinomas. Scatchard analyses of multipoint binding data on 19 of the first 209 tumours, performed by a displacement method, demonstrated that the majority of tumours exhibited 2 classes of binding site, the high-affinity site with an affinity constant (KD) of mean 2 nmol/l (SD 1.3, range 0.44-7 nmol/l), and a low-affinity site, KD mean 9.5 nmol/l (range 6-15.5 nmol/l). Scatchard analysis of multipoint assays using increasing concentrations of 125I-labelled EGF showed that saturation of the high-affinity site occurred in the majority of saturation of the high-affinity site occurred in the majority of tumours at a concentration of labelled EGF of I nM. Comparison of the KD values of the high-affinity site obtained from displacement assays with those obtained by increasing labelled EGF showed that the KD was significantly higher (p = 0.0002) when measured by the latter method. There was no difference in binding capacity of the high-affinity or low-affinity sites by the 2 methods. A 2-point assay with I nM labelled EGF (specific activity approx. 80-130 microCi/microgram) correlated with quantitative values for the high-affinity site from Scatchard analysis (p less than 0.02). There was a strong inverse relationship between EGFr greater than 10 fmol/mg membrane protein (2-point assay) and ER (dextran-coated charcoal method), Chi-squared 2 X 2 contingency table test = 34.027, p less than 0.0001. Follow-up data from 135 patients revealed a strong inverse relationship between EGFr greater than 10 fmol/mg membrane protein and oestrogen receptor (ER) status and a positive correlation with early recurrence and death. Our data describe a reproducible assay for EGFr and show that a cut-off point at 10 fmol/mg allows clinically useful application.


Dopamine and sexual function.
The use of the D1/D2 dopamine receptor agonist apomorphine SL for the treatment of erectile dysfunction provides a strong support in favour of a participation of the dopaminergic system in the control of sexual function. However, the exact involvement of dopamine in sexual motivation and in the control of genital arousal in humans is unknown. In contrast, experimental data suggest an implication of dopamine at all these stages of the copulatory behaviour in rodents. The release of dopamine at the level of the nucleus accumbens, which is innervated by the mesolimbic dopaminergic pathway originating in the ventral tegmental area, is positively implicated in the pre-copulatory or appetitive phase in male rats. There is also a permissive role in the copulatory or consumatory phase for dopamine released at the level of the median pre-optic area, which receives projection from the dopaminergic incertohypothalamic pathway within the hypothalamus. It is noteworthy that these participations of the dopaminergic system are not specific to sexual behaviour but rather reflect the more general involvement of dopamine in the regulation of cognitive, integrative and reward processes. Due to its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behaviour. Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord. The counterpart of such regulation of the genital arousal by dopamine has not yet been established in females. In conclusion, the central dopaminergic system is a key element of the control of sexual function.


An adaptive Fuzzy C-means method utilizing neighboring information for breast tumor segmentation in ultrasound images.
Ultrasound (US) imaging has been widely used in breast tumor diagnosis and treatment intervention. Automatic delineation of the tumor is a crucial first step, especially for the computer-aided diagnosis (CAD) and US-guided breast procedure. However, the intrinsic properties of US images such as low contrast and blurry boundaries pose challenges to the automatic segmentation of the breast tumor. Therefore, the purpose of this study is to propose a segmentation algorithm that can contour the breast tumor in US images. To utilize the neighbor information of each pixel, a Hausdorff distance based fuzzy c-means (FCM) method was adopted. The size of the neighbor region was adaptively updated by comparing the mutual information between them. The objective function of the clustering process was updated by a combination of Euclid distance and the adaptively calculated Hausdorff distance. Segmentation results were evaluated by comparing with three experts' manual segmentations. The results were also compared with a kernel-induced distance based FCM with spatial constraints, the method without adaptive region selection, and conventional FCM. Results from segmenting 30 patient images showed the adaptive method had a value of sensitivity, specificity, Jaccard similarity, and Dice coefficient of 93.60 ± 5.33%, 97.83 ± 2.17%, 86.38 ± 5.80%, and 92.58 ± 3.68%, respectively. The region-based metrics of average symmetric surface distance (ASSD), root mean square symmetric distance (RMSD), and maximum symmetric surface distance (MSSD) were 0.03 ± 0.04 mm, 0.04 ± 0.03 mm, and 1.18 ± 1.01 mm, respectively. All the metrics except sensitivity were better than that of the non-adaptive algorithm and the conventional FCM. Only three region-based metrics were better than that of the kernel-induced distance based FCM with spatial constraints. Inclusion of the pixel neighbor information adaptively in segmenting US images improved the segmentation performance. The results demonstrate the potential application of the method in breast tumor CAD and other US-guided procedures.


Using time-use data to parameterize models for the spread of close-contact infectious diseases.
Social contact patterns are a critical explanatory factor of the spread of close-contact infectious agents. Both indirect (via observed epidemiologic data) and direct (via diaries that record at-risk events) approaches to the measurement of contacts by age have been proposed in the literature. In this paper, the authors discuss the possibilities offered by time-use surveys to measure contact patterns and to explain observed seroprevalence profiles. The authors first develop a methodology to estimate time-of-exposure matrices, and then they apply it to time-use data for the United States (1987-2003). Finally, the authors estimate age-specific transmission parameters for varicella, commonly known as "chickenpox," from age-specific time-of-exposure and seroprevalence data (United States, 1988-1994). The estimated time-of-exposure matrix reveals a strong element of assortativeness by age. In addition, there are peaks of exposure between people who were born one generation apart (i.e., parents and their children). Models based on the estimated age-specific transmission parameters fit the observed patterns of infection of endemically circulating varicella in a satisfactory way. The availability of time-use data for a large number of countries and their potential to supplement contact surveys make the methods developed extremely valuable and suitable for implementation in several different contexts.


The Lived Experience of Welfare Reform in Drug-Using Welfare-Needy Households in Inner-City New York.
Welfare reform has transformed a needs-based family income support into temporary assistance for persons entering the workforce. This paper uses observations from an ethnographic study covering the period from 1995-2001 to examine the impact on drug-using welfare-needy households in inner-city New York. The analysis suggests that studies may underestimate the extent to which substance use is associated with welfare problems. Nearly all of these already distressed households lost their AFDC/TANF benefits, had difficulty with work programs, and were having more difficulty covering expenses. The conclusion highlights ways to better study this population and policy initiatives that could help them reform their impoverished lives for themselves and their children.


A single gene that promotes interaction of a phytopathogenic bacterium with its insect vector, Drosophila melanogaster.
Insects are major vectors of plant and animal disease, and bacterial phytopathogens are often disseminated by flies. We have previously reported that some isolates of the phytopathogenic bacterial species Erwinia carotovora infect Drosophila and activate an immune response. Using a genetic screen, we have now identified two genes that are required by E. carotovora to infect Drosophila. One of these genes has a regulatory role whereas the other, evf, confers an infectious phenotype: its transfer to non-infectious Erwinia strains or to several enterobacteria improves survival in the gut and triggers the immune response. Overexpression of Erwinia virulence factor (evf) allowed bacteria to colonize the apical side of the gut epithelium and in some cases to spread to the body cavity. Our results demonstrate a specific interaction between plant pathogens and flies that promote their dissemination.


Neurosarcoidosis: presentations and management.
Sarcoidosis affects the central nervous system more frequently than previously appreciated. The diagnosis of neurosarcoidosis is often delayed, potentially leading to serious complications. Symptoms, when present, are not specific, may be subtle and resemble those of other neurologic diseases. During the past decade, significant progress has been made in understanding the epidemiology and pathophysiology of neurosarcoidosis, as well as the ability to diagnose and treat this disease. Studies have shown that the optimal diagnostic imaging modality for neurosarcoidosis is magnetic resonance imaging with gadolinium as it enhances visualization of granulomatous infiltration in neural tissue. Subclinical neurosarcoidosis may not be uncommon in patients with sarcoidosis. It is now evident that neurosarcoidosis does not invariably present as a catastrophic event. Adverse effects associated with high-dose systemic corticosteroids, the standard therapy, have discouraged practitioners from initiating treatment in the absence of significant symptomatic neurologic disease. However, other immunosuppressive agents as well newer biologic agents have emerged as an effective, well-tolerated therapeutic alternative to corticosteroids, which are often effective in corticosteroid-recalcitrant cases. Neurologists should be aware of the varying presentations of neurosarcoidosis since early recognition of neurologic involvement in patients with undiagnosed or proven sarcoidosis is currently possible and critical to the prevention of disabling complications.


A population-based study of patterns of care for muscle-invasive bladder cancer in Sweden.
To analyse the management of muscle-invasive bladder cancer in a population-based national register, and specifically to investigate the role of curative therapy (i.e. cystectomy or radiotherapy) in relation to patient, tumour and hospital characteristics. The Swedish Bladder Cancer Register covers more than 90% of all patients in the country who have been diagnosed with such disease since 1997. Results from 1997-2003 were analysed regarding curative-intent treatment given within 3-6 months of diagnosis of muscle-invasive bladder cancer. In total, 3463 patients with clinical T2-T4 bladder cancer were included in the analysis. Of those patients, 1426 (41%) received curative-intent treatment in the form of radiotherapy (285, 20%) or cystectomy (1141, 80%). Male gender, age < 76 years, favourable TNM category and registration at a high-volume hospital were associated with such treatment. Curative-intent treatment was given to significantly more patients registered at high-volume hospitals (1003/2227, 45%) than at low-volume hospitals (423/1235, 34%) (chi(2)=37.7, p<0.00001). Cystectomy was performed more often in those registered at high-volume than at low-volume hospitals (826/2227, 37%, and 316/1235, 26%, respectively, chi(2)=47.3, p<0.00001). Lower rates of curative-intent treatment were found in patients registered at low-volume than at high-volume facilities, and the same was seen when comparing females with males, and patients aged 76-80 years with younger patients. Since many of these bladder cancer patients were registered at and eventually treated at hospitals handling fewer than 10 such cases annually, it seems desirable to concentrate treatment of this disease at more specialized centres.


Image algebra representation of parallel optical binary arithmetic.
A binary image algebra (BIA) that gives a mathematical description of parallel processing operations is described. Rigorous and concise BIA representations of parallel arithmetic and symbolic substitution operations are given. A sequence of programming steps for implementation of these operations on a parallel architecture is specified by the BIA representation. Examples of arithmetic operations implemented on a digital optical cellular image processor architecture are given.


Influence of time to diagnosis of severe influenza on antibiotic use, length of stay, isolation precautions, and mortality: a retrospective study.
Timely diagnosis of influenza infection in patients might help reduce antibiotic use during influenza seasons and, consequently, antibiotic selection pressure. In this retrospective cohort study, we aimed to evaluate whether time to influenza diagnosis in patients with severe influenza is associated with the duration of antibiotic therapy. We retrospectively included all hospitalized patients >16 years who tested positive for influenza A or B by polymerase chain reaction during influenza seasons 2013/2014 or 2014/2015 at the University Hospital Zurich. The primary aim was to assess the association between timing of laboratory-confirmed influenza diagnosis and duration of antibiotic therapy. Secondary outcomes were length of hospital stay, duration of isolation precautions, and mortality. Early diagnosis was defined as laboratory confirmation on the day of or the day after hospital admission or symptom onset. A total of 126 patients were included (median age 57 years). Timing of influenza diagnosis was not associated with the duration of antibiotic treatment, the duration of isolation precautions, or mortality. Early influenza was associated with reduced length of hospital stay (median 7 vs 9 days [P=.014]) in patients with community-acquired influenza. Although the duration of antibiotic therapy and mortality were found unaffected by early influenza diagnosis, our data indicate that it is linked with a reduction in the length of hospitalization in patients with community-acquired influenza. This highlights a need to also fully understand the effect of time to diagnosis of bacterial pathogens on antibiotic prescribing patterns in order to exploit the potential of early influenza diagnosis in patient care.


Optimising use of 4D-CT phase information for radiomics analysis in lung cancer patients treated with stereotactic body radiotherapy.
Purpose. 4D-CT is routine imaging for lung cancer patients treated with stereotactic body radiotherapy. No studies have investigated optimal 4D phase selection for radiomics. We aim to determine how phase data should be used to identify prognostic biomarkers for distant failure, and test whether stability assessment is required. A phase selection approach will be developed to aid studies with different 4D protocols and account for patient differences.Methods. 186 features were extracted from the tumour and peritumour on all phases for 258 patients. Feature values were selected from phase features using four methods: (A) mean across phases, (B) median across phases, (C) 50% phase, and (D) the most stable phase (closest in value to two neighbours), coined personalised selection. Four levels of stability assessment were also analysed, with inclusion of: (1) all features, (2) stable features across all phases, (3) stable features across phase and neighbour phases, and (4) features averaged over neighbour phases. Clinical-radiomics models were built for twelve combinations of feature type and assessment method. Model performance was assessed by concordance index (c-index) and fraction of new information from radiomic features.Results. The most stable phase spanned the whole range but was most often near exhale. All radiomic signatures provided new information for distant failure prediction. The personalised model had the highest c-index (0.77), and 58% of new information was provided by radiomic features when no stability assessment was performed.Conclusion. The most stable phase varies per-patient and selecting this improves model performance compared to standard methods. We advise the single most stable phase should be determined by minimising feature differences to neighbour phases. Stability assessment over all phases decreases performance by excessively removing features. Instead, averaging of neighbour phases should be used when stability is of concern. The models suggest that higher peritumoural intensity predicts distant failure.


Care and caring culture as experienced by nurses working in different care environments: a phenomenological-hermeneutic study.
The aim is to understand and develop the concept of care and caring culture and to do so based on the empirical/phenomenological standpoint of nurses' lived experiences of working in different environments. Culture, care and caring are significant concepts mentioned and used in connection with nursing practice. In the nursing literature, the 'caring culture' as a concept is mostly taken for granted, and it is up to the reader to determine what caring culture means. A phenomenological-hermeneutic method was used to uncover the meaning of lived experiences though interpretation of interviews transcribed as text. Seventeen nurses working on different wards were interviewed in 2006. A follow-up focus-group discussion was conducted with seven of the nurses 1 year later for validation of the findings. Thematic analyses revealed five themes: you have to adapt to the existing care culture; seeing the invisible; being yourself; the strong personalities; the patients must adapt themselves to the circumstances. Adaptation to unwritten routines entails adaptation to the culture and the common value system. On wards described as "homelike", nurses may act in a way that reflects their own values. The care and caring culture can be understood from the perspective of what it means to care and from the perspective of how care provision is accomplished. To attain a caring culture founded on certain values, for example caritas, love and charity, we must first understand how the organization and personnel understand caring.


Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is still increasing in Europe and the prognosis remains poor. We investigated the oncogenic function of signal transducer and activator of transcription 1 (STAT1) in MPM in more detail. A miRNA profiling was performed on 52 MPM tissue samples. Upregulated miRNAs (targeting SOCS1/3) were knocked-down using miRNA inhibitors. mRNA expression levels of STAT1/3, SOCS1/3 were detected in MPM cell lines. STAT1 has been knocked-down using siRNA and qPCR was used to detect mRNA expression levels of all JAK/STAT family members and genes that regulate them. An immunohistochemical staining was performed to detect the expression of caspases. STAT1 was upregulated and STAT3 was downregulated, SOCS1/3 protein was not detected but it was possible to detect SOCS1/3 mRNA in MPM cell lines. The upregulated miRNAs were successfully knocked-down, however the expected effect on SOCS1 expression was not detected. STAT1 knock-down had different effects on STAT3/5 expression. Caspase 3a and 8 expression was found to be increased after STAT1 knock-down. The physiologic regulation of STAT1 via SOCS1 is completely lost in MPM and it does not seem that the miRNAs identified by now, do inhibit the expression of SOCS1. MPM cell lines compensate STAT1 knock-down by increasing the expression of STAT3 or STAT5a, two genes which are generally considered to be oncogenes. And much more important, STAT1 knock-down induces apoptosis in MPM cell lines and STAT1 might therefore be a target for therapeutic intervention.


Quantitative kinematic characterization of reaching impairments in mice after a stroke.
Kinematic analysis of reaching movements is increasingly used to evaluate upper extremity function after cerebrovascular insults in humans and has also been applied to rodent models. Such analyses can require time-consuming frame-by-frame inspections and are affected by the experimenter's bias. In this study, we introduce a semi-automated algorithm for tracking forepaw movements in mice. This methodology allows us to calculate several kinematic measures for the quantitative assessment of performance in a skilled reaching task before and after a focal cortical stroke. Mice were trained to reach for food pellets with their preferred paw until asymptotic performance was achieved. Photothrombosis was then applied to induce a focal ischemic injury in the motor cortex, contralateral to the trained limb. Mice were tested again once a week for 30 days. A high frame rate camera was used to record the movements of the paw, which was painted with a nontoxic dye. An algorithm was then applied off-line to track the trajectories and to compute kinematic measures for motor performance evaluation. The tracking algorithm proved to be fast, accurate, and robust. A number of kinematic measures were identified as sensitive indicators of poststroke modifications. Based on end-point measures, ischemic mice appeared to improve their motor performance after 2 weeks. However, kinematic analysis revealed the persistence of specific trajectory adjustments up to 30 days poststroke, indicating the use of compensatory strategies. These results support the use of kinematic analysis in mice as a tool for both detection of poststroke functional impairments and tracking of motor improvements following rehabilitation. Similar studies could be performed in parallel with human studies to exploit the translational value of this skilled reaching analysis.


Associations between dialysate sodium concentration and plasma sodium concentration of dogs receiving intermittent hemodialysis treatments.
OBJECTIVE To compare dialysate sodium concentration and patient plasma sodium concentration of dogs during intermittent hemodialysis treatments. SAMPLE 211 intermittent hemodialysis treatments performed on 40 client-owned dogs for the management of dialysis-dependent uremia. PROCEDURES Medical records were reviewed to determine the plasma sodium concentration of each dog before and after routine hemodialysis treatments. Associations between detected changes in plasma sodium concentration and dialysate sodium concentration were evaluated by use of Spearman rank correlations and linear regression analysis. RESULTS Significant linear correlations were found between the dialysate sodium concentration and patient sodium concentration. The starting dialysate-to-patient sodium gradient was associated with the strongest correlation to the change in patient sodium concentration at the end of the dialysis session. Modest correlations existed between the dialysate sodium concentration and postdialysis patient sodium concentration as well as between the predialysis dialysate-to-patient sodium gradient and postdialysis dialysate-to-patient sodium gradient. CONCLUSIONS AND CLINICAL RELEVANCE The dialysate sodium concentration was correlated with the patient sodium concentration in dogs, and the dialysate-to-patient sodium gradient could be used to further refine this association to predict the postdialysis patient sodium concentration and potentially manage dysnatremia during hemodialysis. Prospective studies should be performed to determine how these associations can be used to correct aberrations as well as to avoid unwanted alterations in patient sodium concentrations.


Pyoderma gangrenosum complicating bilateral total knee arthroplasty.
Pyoderma gangrenosum is an ulcerative, necrotic dermatosis of unknown etiology. It is frequently associated with inflammatory, hematologic, or neoplastic disease. Clinical and physical evaluation can imitate postoperative wound infections. This article reports a case of pyoderma gangrenosum in a patient who underwent bilateral total knee arthroplasty. Her postoperative course was complicated by wound dehiscence and ulceration in both knees. Her condition deteriorated despite debridements and antibiotic therapy. Deep intraoperative cultures were all negative. Once the diagnosis of pyoderma gangrenosum was established and once appropriate treatment with steroids was initiated, her condition improved. The diagnosis of pyoderma gangrenosum should be considered in patients with wound deterioration who remain culture-negative and fail to respond to debridement and antibiotic treatment. This case report highlights the presentation of pyoderma gangrenosum and its ability to be misdiagnosed as infection. A delay in treatment may result in unnecessary surgery that will further exacerbate this inflammatory condition.


Combined iron/folic acid supplements and malaria prophylaxis reduce neonatal mortality in 19 sub-Saharan African countries.
In nonmalaria regions, iron/folic acid supplementation during pregnancy protects newborns against preterm delivery and early neonatal death. Other studies from malaria-endemic areas have reported an adverse effect of iron supplements on malaria prevalence in pregnant women. We examined the association between iron/folic acid supplements and prenatal antimalaria prophylaxis on neonatal mortality in malaria-endemic countries of sub-Saharan Africa. This analysis used the most recent data from Demographic and Health Surveys of 19 malaria-endemic countries in sub-Saharan Africa. Survival information of 101,636 singleton live-born infants from the most recent delivery of ever-married women < or =5 y before each survey was examined. The effect of each potential predictor on neonatal deaths was analyzed by using Cox proportional hazards regression models. Infants whose mothers received any iron/folic acid supplements and sulfadoxine-pyrimethamine intermittent preventive treatment (SP-IPT(p)) for malaria during pregnancy were significantly protected from neonatal death [hazard ratio (HR): 0.76; 95% CI: 0.58, 0.99]. The protective effect was not significant in mothers who received only iron/folic acid supplements (HR: 0.90; 95% CI: 0.73, 1.12) or only SP-IPT(p) (HR: 1.08; 95% CI: 0.74, 1.57). Among the sociodemographic and birth characteristics, factors that significantly increased the risk of neonatal death included first-born infants, a birth interval of <2 y, maternal age at delivery of > or =30 y, smaller than average-sized infants, and male infants. The use of antenatal iron/folic acid supplements combined with appropriate intermittent preventive treatment of malaria during pregnancy is an important intervention to reduce neonatal mortality in malaria-endemic regions.


Behavioral and synaptic circuit features in a zebrafish model of fragile X syndrome.
Fragile X syndrome (FXS) is the most frequent inherited form of human mental retardation. It is characterized by cognitive impairment and physical and behavioral problems and is caused by the silencing of fmr1 transcription and the absence of the fmr1 protein (FMRP). Recently, animal models of FXS have greatly facilitated the investigation of the molecular and cellular mechanisms of this loss-of-function disorder. The present study was aimed to further characterize the role of FMRP in behavior and synaptic function by using fmr1 knockout zebrafish. In adult zebrafish, we found that fmr1 knockout produces the anxiolytic-like responses of increased exploratory behavior in light/dark and open-field tests and avoidance learning impairment. Furthermore, electrophysiological recordings from telencephalic slice preparations of knockout fish displayed markedly reduced long-term potentiation and enhanced long-term depression compared to wild-type fish; however, basal glutamatergic transmission and presynaptic function at the lateral (Dl) and medial (Dm) division of the dorsal telencephalon synapse remained normal. Taken together, our study not only evaluates the mechanism of FRMP but also suggests that zebrafish have valuable potential as a complementary vertebrate model in studying the molecular pathogenesis of human fragile X syndrome.


Intercerebellar coupling contributes to bimanual coordination.
Compared to unimanual task execution, simultaneous bimanual tapping tasks are associated with a significantly reduced intertap variability. It has been suggested that this bimanual advantage is based on the integration of timing signals which otherwise control each hand independently. Although its functional and anatomic foundations are poorly understood, functional coupling between cerebellar hemispheres might be behind this process. Because the execution of fast alternating fingertaps increases intertap variability, it is hypothesized that intercerebellar coupling is reduced in such tasks. To shed light on the functional significance of intercerebellar coupling, 14 right-handed subjects performed unimanual right, bimanual simultaneous, and bimanual alternating synchronization tasks with respect to a regular auditory pacing signal. In all conditions, within-hand intertap interval was 500 msec. Continuous neuromagnetic activity, using a 122-channel wholehead neuromagnetometer and surface electromyograms of the first dorsal interosseus muscle of both hands, were recorded. For data analysis, we used the analysis tool Dynamic Imaging of Coherent Sources, which provides a tomographic map of cerebromuscular and cerebrocerebral coherence. Analysis revealed a bilateral cerebello-thalamo-cortical network oscillating at alpha (8-12 Hz) and beta (13-24 Hz) frequencies associated with bimanual synchronization. In line with our hypothesis, coupling between cerebellar hemispheres was restricted to simultaneous task execution. This result implies that intercerebellar coupling is key for the execution of simultaneous bimanual movements. Although the criticality of a specific magneto-encephalography pattern for behavioral changes should be interpreted with caution, data suggest that intercerebellar coupling possibly represents the functional foundation of the bimanual advantage.


Arterial Thrombosis Is Accompanied by Elevated Mitogen-Activated Protein Kinase (MAPK) and Cyclooxygenase-2 (COX-2) Expression via Toll-Like Receptor 4 (TLR-4) Activation by S100A8/A9.
BACKGROUND The aim of this study was to determine the involvement of S100A8/A9 in the development of arterial thrombosis. MATERIAL AND METHODS A total of 303 patients were enrolled in this study, with 110 having acute coronary syndrome (ACS) and 110 having coronary heart disease (CHD), and 83 subjects served as healthy blood donors. The concentrations of Toll-like receptor 4 (TLR-4), cyclooxygenase-2 (COX-2), and S100A8/A9 protein were determined in the sera of the participants and in peripheral blood mononuclear cells (PBMCs) derived from a rat carotid artery thrombosis model and in human aortic endothelial cells (HAECs). The mitogen-activated protein kinase (MAPK) inhibitor SB203580 and the TLR-4 blocker CLI-095 were used to investigate the role of the TLR-4-MAPK-COX2 signaling axis in thrombosis. RESULTS The levels of COX-2, TLR-4, and S100A8/A9 in the sera of patients with ACS and CHD were significantly higher than in healthy controls (P<0.05). S100A8/A9 expression was significantly correlated with TLR-4 and COX-2 in the ACS group and with TLR-4 in the CHD group. In the rat carotid thrombosis model, the expressions of TLR-4, COX-2, and p-p38 MAPK significantly increased until 14 days after thrombosis induction, whereas S100A8/A9 expression increased until day 7, but then decreased. Administration of SB203580 to rats reduced COX-2 expression in PBMCs after thrombosis induction, and incubation of HAECs with CLI-095 reduced their p-p38 MAPK and COX-2 response to S100A8/A9 stimulation. CONCLUSIONS S100A8/A9 is upregulated after blood vessel injury and is enhanced in combination with TLR-4 COX-2 induction via p38 MAPK activation.


Therapeutic rescue of misfolded mutants: validation of primary high throughput screens for identification of pharmacoperone drugs.
Functional rescue of misfolded mutant receptors by small non-peptide molecules has been demonstrated. These small, target-specific molecules (pharmacological chaperones or "pharmacoperones") serve as molecular templates, promote correct folding and allow otherwise misfolded mutants to pass the scrutiny of the cellular quality control system (QCS) and be expressed at the plasma membrane (PM) where they function similarly to wild type (WT) proteins. In the case of the gonadotropin releasing hormone receptor (GnRHR), drugs that rescue one mutant typically rescue many mutants, even if the mutations are located at distant sites (extracellular loops, intracellular loops, transmembrane helices). This increases the value of these drugs. These drugs are typically identified, post hoc, from "hits" in screens designed to detect antagonists or agonists. The therapeutic utility of pharmacoperones has been limited due to the absence of screens that enable identification of pharmacoperones per se. We describe a generalizable primary screening approach for pharmacoperone drugs based on measurement of gain of activity in stable HeLa cells stably expressing the mutants of two different model G-protein coupled receptors (GPCRs) (hGnRHR[E(90)K] or hV2R[L(83)Q]). These cells turn off expression of the receptor mutant gene of interest in the presence of tetracycline and its analogs, which provides a convenient means to identify false positives. The methods described and characterized here provide the basis of novel primary screens for pharmacoperones that detect drugs that rescue GPCR mutants of specific receptors. This approach will identify structures that would have been missed in screens that were designed to select only agonists or antagonists. Non-antagonistic pharmacoperones have a therapeutic advantage since they will not compete for endogenous agonists and may not have to be washed out once rescue has occurred and before activation by endogenous or exogenous agonists.


Prevention of anal condyloma with quadrivalent human papillomavirus vaccination of older men who have sex with men.
The quadrivalent human papillomavirus vaccine (qHPV) is FDA-approved for use in males 9 to 26 years old to prevent anogenital condyloma. The objective of this study is to determine if qHPV is effective at preventing anal condyloma among men who have sex with men (MSM) aged 26 years and older. This post-hoc analysis of a nonconcurrent cohort study evaluated 210 patients without history of anal condyloma and 103 patients with previously-treated anal condyloma recurrence-free for at least 12 months prior to vaccination/time zero. We determined the rate of anal condyloma development in vaccinated versus unvaccinated patients. 313 patients with mean age 42 years were followed for median 981 days. During 773.6 person-years follow-up, condyloma developed in 10 (8.6%) vaccinated patients (incidence of 3.7 per 100 person-years) and 37 (18.8%) unvaccinated patients (incidence 7.3 per 100 person-years; p = 0.05). Multivariable hazards ratio showed that qHPV was associated with decreased risk of anal condyloma development (HR 0.45; 95% CI 0.22-0.92; p = 0.03). History of anal condyloma was associated with increased risk of anal condyloma development (HR 2.28; 95% CI 1.28-4.05; p = 0.005), as was infection with oncogenic HPV (HR 3.87; 95% CI 1.66-9.03; p = 0.002). Among MSM 26 years of age and older with and without history of anal condyloma, qHPV reduces the risk of anal condyloma development. A randomized controlled trial is needed to confirm these findings in this age group.


Host defences to Citrobacter rodentium.
Citrobacter rodentium is a natural non-invasive bacterial pathogen which infects the distal colon of mice. It uses the same molecular mechanisms of type III secretion as human enteropathogenic and enterohemorrhagic Escherichia coli to colonise the epithelial cells of the gut and is therefore an ideal model to study host-bacterial pathogen interactions in vivo. Infection elicits mucosal inflammation with similarities to inflammatory bowel disease, and so it is a readily accessible model to investigate the relationship between inflammation and anti-bacterial immunity in the gut.


Molecular conductors from bis(ethylenedithio)tetrathiafulvalene with tris(oxalato)rhodate.
This article reports a family of new radical-cation salts of bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) with tris(oxalato)rhodate: three salts with the formula β''-(BEDT-TTF)4[(cation)Rh(C2O4)3]·solvent (solvent = fluorobenzene, chlorobenzene, or bromobenzene) and one with the formula pseudo-κ-(BEDT-TTF)4[(NH4)Rh(C2O4)3]·benzonitrile. We report here the syntheses, crystal structures, electrical properties and Raman spectroscopy of these new molecular conductors. The bromobenzene salt shows a decrease in resistivity below 2.5 K indicative of a superconducting transition and a Shubnikov-de Haas oscillation with a frequency of 232 T and effective mass m* of 1.27me.


Mechanics of capillary forming of aligned carbon nanotube assemblies.
Elastocapillary self-assembly is emerging as a versatile technique to manufacture three-dimensional (3D) microstructures and complex surface textures from arrangements of micro- and nanoscale filaments. Understanding the mechanics of capillary self-assembly is essential to engineering of properties such as shape-directed actuation, anisotropic wetting and adhesion, and mechanical energy transfer and dissipation. We study elastocapillary self-assembly (herein called "capillary forming") of carbon nanotube (CNT) microstructures, combining in situ optical imaging, micromechanical testing, and finite element modeling. By imaging, we identify sequential stages of liquid infiltration, evaporation, and solid shrinkage, whose kinetics relate to the size and shape of the CNT microstructure. We couple these observations with measurements of the orthotropic elastic moduli of CNT forests to understand how the dynamic of shrinkage of the vapor-liquid interface is coupled to the compression of the forest. We compare the kinetics of shrinkage to the rate of evporation from liquid droplets having the same size and geometry. Moreover, we show that the amount of shrinkage during evaporation is governed by the ability of the CNTs to slip against one another, which can be manipulated by the deposition of thin conformal coatings on the CNTs by atomic layer deposition (ALD). This insight is confirmed by finite element modeling of pairs of CNTs as corrugated beams in contact and highlights the coupled role of elasticity and friction in shrinkage and stability of nanoporous solids. Overall, this study shows that nanoscale porosity can be tailored via the filament density and adhesion at contact points, which is important to the development of lightweight multifunctional materials.


Association between maternal haemoglobin concentrations and maternal and neonatal outcomes: the prospective, observational, multinational, INTERBIO-21st fetal study.
Anaemia in pregnancy is a global health problem with associated maternal and neonatal morbidity and mortality. We aimed to investigate the association between maternal haemoglobin concentrations during pregnancy and the risk of adverse maternal and neonatal outcomes. In this prospective, observational, multinational, INTERBIO-21st fetal study conducted at maternity units in Brazil, Kenya, Pakistan, South Africa, and the UK, we enrolled pregnant women (aged ≥18 years, BMI <35 kg/m2, natural conception, and singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. At each 5±1 weekly visit until delivery, information was collected about the pregnancy, as well as the results of blood tests taken as part of routine antenatal care, including haemoglobin values. The outcome measures were maternal (gestational diabetes, pregnancy-induced hypertension, and preterm premature rupture of membranes) and neonatal outcomes (small for gestational age, preterm birth, and acute respiratory distress syndrome). Between Feb 8, 2012, and Nov 30, 2019, 2069 women (mean age 30·7 years [SD 5·0]) had at least one routinely haemoglobin concentration measured at 14-40 weeks' gestation, contributing 4690 haemoglobin measurements for the analysis. Compared with a haemoglobin cutoff of 110 g/L, the risk was increased more than two-fold for pregnancy-induced hypertension at haemoglobin concentrations of 170 g/L (risk ratio [RR] 2·29 [95% CI 1·19-4·39]) and higher, for preterm birth at haemoglobin concentrations of 70 g/L (RR 2·04 [95% CI 1·20-3·48]) and 165 g/L (RR 2·06 [95% CI 1·41-3·02]), and for acute respiratory distress syndrome at haemoglobin concentrations of 165 g/L (RR 2·84 [95% CI 1·51-5·35]). Trimester-specific results are also presented. Our data suggests that the current WHO haemoglobin cutoffs are associated with reduced risk of adverse maternal and neonatal outcomes. The current haemoglobin concentration cutoffs during pregnancy should not only consider thresholds for low haemoglobin concentrations that are associated with adverse outcomes but also define a threshold for high haemoglobin concentrations given the U-shaped relationship between haemoglobin concentration and adverse neonatal and maternal outcomes. Bill & Melinda Gates Foundation.


Influence of Hypoxic Interval Training and Hyperoxic Recovery on Muscle Activation and Oxygenation in Connection with Double-Poling Exercise.
Here, we evaluated the influence of breathing oxygen at different partial pressures during recovery from exercise on performance at sea-level and a simulated altitude of 1800 m, as reflected in activation of different upper body muscles, and oxygenation of the m. triceps brachii. Ten well-trained, male endurance athletes (25.3±4.1 yrs; 179.2±4.5 cm; 74.2±3.4 kg) performed four test trials, each involving three 3-min sessions on a double-poling ergometer with 3-min intervals of recovery. One trial was conducted entirely under normoxic (No) and another under hypoxic conditions (Ho; FiO2 = 0.165). In the third and fourth trials, the exercise was performed in normoxia and hypoxia, respectively, with hyperoxic recovery (HOX; FiO2 = 1.00) in both cases. Arterial hemoglobin saturation was higher under the two HOX conditions than without HOX (p<0.05). Integrated muscle electrical activity was not influenced by the oxygen content (best d = 0.51). Furthermore, the only difference in tissue saturation index measured via near-infrared spectroscopy observed was between the recovery periods during the NoNo and HoHOX interventions (P<0.05, d = 0.93). In the case of HoHo the athletes' Pmean declined from the first to the third interval (P < 0.05), whereas Pmean was unaltered under the HoHOX, NoHOX and NoNo conditions. We conclude that the less pronounced decline in Pmean during 3 x 3-min double-poling sprints in normoxia and hypoxia with hyperoxic recovery is not related to changes in muscle activity or oxygenation. Moreover, we conclude that hyperoxia (FiO2 = 1.00) used in conjunction with hypoxic or normoxic work intervals may serve as an effective aid when inhaled during the subsequent recovery intervals.


Geographic disparities in COVID-19 case rates are not reflected in seropositivity rates using a neighborhood survey in Chicago.
To date, COVID-19 case rates are disproportionately higher in Black and Latinx communities across the US, leading to more hospitalizations, and deaths in those communities. These differences in case rates are evident in comparisons of Chicago neighborhoods with differing race and/or ethnicities of their residents. Disparities could be due to neighborhoods with more adverse health outcomes associated with poverty and other social determinants of health experiencing higher prevalence of SARS-CoV-2 infection or due to greater morbidity and mortality resulting from equivalent SARS-CoV-2 infection prevalence. We surveyed five pairs of adjacent ZIP codes in Chicago with disparate COVID-19 case rates for highly specific and quantitative serologic evidence of any prior infection by SARS-CoV-2 to compare with their disparate COVID-19 case rates. Dried blood spot samples were self-collected at home by internet-recruited participants in summer 2020, shortly after Chicago's first wave of the COVID-19 pandemic. Pairs of neighboring ZIP codes with very different COVID-19 case rates had similar seropositivity rates for anti-SARS-CoV-2 receptor binding domain IgG antibodies. Overall, these findings of comparable exposure to SARS-CoV-2 across neighborhoods with very disparate COVID-19 case rates are consistent with social determinants of health, and the co-morbidities related to them, driving differences in COVID-19 rates across neighborhoods.


Digital radiography density measurements in differentiation between periapical granulomas and radicular cysts.
The distinction between radicular cysts and apical granulomas is a matter of considerable importance in making a treatment decision. Because there are no clearly defined radiographic criteria, the distinction is made on the grounds of size. However, it has been suggested that cysts can be distinguished from granulomas on the basis of their radiometric density. The results of previous studies have proved conflicting. To determine possibilities of application of digital radiography density measurements in differentiation of periapical granulomas and radicular cysts of inflammatory origin. The material consisted of 355 digital periapical radiograms obtained using Digora, RVG and Dixi 2 digital radiography systems in patients aged 20 to 84, divided into two groups: 259 granulomas and 102 radicular cysts. By means of Digora 2.0 software there were measured maximum and minimum densities along a line, then there was calculated the difference between maximum and minimum density. The largest dimensions of the lesions were measured - perpendicular and parallel to the root canal axis. It was proved that to some extent it was possible to differentiate cystic granulomas and radicular cysts on the basis of the difference between maximum and minimum density in linear measurement - when the difference exceeded 85.6 the lesion was a cyst and when it was below 45.9 a granuloma was diagnosed. Combination of two criteria - the calculated difference between densities and the largest dimension of a lesion, increased diagnostic possibilities of radiological differentiation of granulomas and radicular cysts.


Arithmetic processing in the brain shaped by cultures.
The universal use of Arabic numbers in mathematics raises a question whether these digits are processed the same way in people speaking various languages, such as Chinese and English, which reflect differences in Eastern and Western cultures. Using functional MRI, we demonstrated a differential cortical representation of numbers between native Chinese and English speakers. Contrasting to native English speakers, who largely employ a language process that relies on the left perisylvian cortices for mental calculation such as a simple addition task, native Chinese speakers, instead, engage a visuo-premotor association network for the same task. Whereas in both groups the inferior parietal cortex was activated by a task for numerical quantity comparison, functional MRI connectivity analyses revealed a functional distinction between Chinese and English groups among the brain networks involved in the task. Our results further indicate that the different biological encoding of numbers may be shaped by visual reading experience during language acquisition and other cultural factors such as mathematics learning strategies and education systems, which cannot be explained completely by the differences in languages per se.


Influence of smoking on gingival crevicular fluid cytokines in severe chronic periodontitis.
The aim of this study was to compare the expression of 22 chemokines and cytokines in gingival crevicular fluid (GCF) from smokers and non-smokers with periodontitis and periodontally healthy control subjects. Forty subjects with generalized severe chronic periodontitis (20 smokers and 20 non-smokers) and 12 periodontally healthy control subjects participated in this study. Four diseased and two healthy sites were selected from each of the periodontitis subjects. GCF samples were collected and cytokines analysed utilizing a multiplexed immunoassay (Luminex(®) ). Statistical analyses employed non-parametric tests including the Mann-Whitney and Wilcoxon matched-pairs signed-rank tests. Compared with healthy control subjects, GCF in subjects with chronic periodontitis contained significantly higher amounts of interleukin (IL)-1α, IL-1β, IL-6, IL-12(p40) (pro-inflammatory cytokines); IL-8, macrophage chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, regulated on activation normal T-cell expressed and secreted (RANTES) (chemokines); IL-2, IFN-γ, IL-3, IL-4 (Th1/Th2 cytokines); IL-15 [regulator of T-cells and natural killer (NK) cells]. Smokers displayed decreased amounts of pro-inflammatory cytokines [IL-1α, IL-6, IL-12(p40)], chemokines (IL-8, MCP-1, MIP-1, RANTES), and regulators of T-cells and NK cells (IL-7, IL-15). Periodontitis subjects had significantly elevated cytokine and chemokine profiles. Smokers exhibited a decrease in several pro-inflammatory cytokines and chemokines and certain regulators of T-cells and NK-cells. This reflects the immunosuppressant effects of smoking which may contribute to an enhanced susceptibility to periodontitis.


Decreased levels of 13-hydroxyoctadecadienoic acid (13-HODE) dehydrogenase in neoplastic tissue of human colon biopsies.
Recent studies have identified a role for the oxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (13-HODE) in cell proliferation. The enzyme 13-HODE dehydrogenase catalyzes the conversion of 13-HODE to 13-oxooctadecadienoic acid. This enzyme has been shown to correlate with the degree of differentiation of intestinal cells in both in vitro and in vivo models. Higher enzyme levels are found in more differentiated cell types. The present study was done to determine if enzyme levels of 13-HODE dehydrogenase are predictive of the differentiation status of biopsies from human colonic mucosa. Twenty-eight patients who underwent diagnostic colonoscopy (10 patients with adenocarcinoma and 18 with adenomatous polyps) had biopsies taken from both normal rectal mucosa and neoplastic mucosa. The determination of 13-HODE dehydrogenase activity was conducted by high-performance liquid chromatography analysis of all biopsy samples. Sixteen of the 18 patients with polyps had lower 13-HODE dehydrogenase activity in the adenoma than in the uninvolved rectal mucosa (P = 0.001). The colon adenocarcinomas also had less 13-HODE dehydrogenase activity in the cancer biopsy tissue than in uninvolved rectal mucosa (P = 0.041) These data are consistent with a role for 13-HODE dehydrogenase in intestinal cell differentiation. Understanding the precise role of this enzymatic reaction could be important potentially in the therapy and biology of colon cancer. In addition, measurements of 13-HODE dehydrogenase may be a useful parameter by which to ascertain the differentiation status of intestinal cells in vitro.


A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion.
The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of a levodopa/carbidopa gel (Duodopa) to examine pharmacological properties of this treatment. The modeling involved pooling data from 3 studies (on advanced Parkinson disease) and fixing some parameters to values found in literature. The first study involved 12 patients studied on 3 occasions each and was previously published. The second study involved 3 patients on 2 occasions. A bolus dose was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function on a 7-point treatment response scale ranging from "very off" to "very hyperkinetic") were collected until the clinical effect returned to baseline. The third study involved 5 patients on 3 occasions receiving 5 different dose levels. Different structural models were evaluated using the nonlinear mixed-effects modeling program NONMEM VI. Population mean parameter values, and interindividual, interoccasion, and residual variabilities were estimated. Absorption of the levodopa/carbidopa gel can be adequately described with first-order absorption with bioavailability and lag time. Estimated population parameter values were a mean absorption time of 28.5 minutes, a lag time of 2.9 minutes, and a bioavailability of 88%. The pharmacodynamic model for motor ratings had the following population values: a half-life of effect delay of 21 minutes, a concentration at 50% effect of 1.55 mg/L, an Emax of 2.39 U on the treatment response scale, and a sigmoidicity of the Emax function of 11.6. For the typical unmedicated subject, it will take 51.4 minutes until the peak levodopa effect is reached after a bolus dose. This delay is, like the magnitude of the effect, highly variable in this patient group. The residual error magnitudes of 20% for levodopa concentrations and 0.92 U (SD) for motor ratings indicate that the models developed provide predictions of a relevant quality. The developed model may be a first step toward model-guided treatment individualization of duodenal infusion of levodopa.


Age-dependent structural connectivity effects in fragile x premutation.
To examine the effects of premutation alleles on major brain fiber tracts in males. Cross-sectional study performed in 2007-2009. Institutional practice. Fifteen younger (18-45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X-associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level. Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter. In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum. The findings revealed widespread alterations in structural connectivity associated with fragile X-associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder. Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.


Composition and Comparison of the Ocular Surface Microbiome in Infants and Older Children.
Unlike other microbiomes of the body, the composition of the ocular surface microbiome (OSM) in children has yet to be thoroughly explored. Our goal was to evaluate the OSM in young infants and compare its composition to older children using both culture dependent and independent methodologies to assess for differences with age. Prospective, observational, cross-sectional study of children <18 years of age at a university-based institution. The mucosal surfaces of both eyes, nose and throat were swabbed with a forensic-quality swab. Half of the swab was plated for culture and the other half underwent 16S sequencing. Culture results and microbiome diversity were analyzed. Fifty patients (mean age 37 months, range 1-168 months) were enrolled. Forty-seven eyes of 30 patients had positive cultures; four eyes grew >1 species. Culture positive patients were older (43 vs. 29 months, P = 0.19). Additionally, older children had greater diversity than children under 6 months of age by 16S sequencing (P = 0.05). Staphylococcus species were predominant by culture (35/52 isolates) and by 16S sequencing. The OSM was fairly similar to the nose microbiome, whereas the throat microbiome differed significantly and had a higher abundance of Streptococcaceae (P = 0.001). The OSM is predominantly composed of Staphylococcus species in children, as demonstrated by both culture dependent and culture independent methods. Older children were more likely to have growth on culture and have more a complex bacterial milieu with 16S sequencing. 16S sequencing provides more robust information regarding the composition of the microbiomes than culture dependent methods.


Protection against divergent influenza H1N1 virus by a centralized influenza hemagglutinin.
Influenza poses a persistent worldwide threat to the human population. As evidenced by the 2009 H1N1 pandemic, current vaccine technologies are unable to respond rapidly to this constantly diverging pathogen. We tested the utility of adenovirus (Ad) vaccines expressing centralized consensus influenza antigens. Ad vaccines were produced within 2 months and protected against influenza in mice within 3 days of vaccination. Ad vaccines were able to protect at doses as low as 10(7) virus particles/kg indicating that approximately 1,000 human doses could be rapidly generated from standard Ad preparations. To generate broadly cross-reactive immune responses, centralized consensus antigens were constructed against H1 influenza and against H1 through H5 influenza. Twenty full-length H1 HA sequences representing the main branches of the H1 HA phylogenetic tree were used to create a synthetic centralized gene, HA1-con. HA1-con minimizes the degree of sequence dissimilarity between the vaccine and existing circulating viruses. The centralized H1 gene, HA1-con, induced stronger immune responses and better protection against mismatched virus challenges as compared to two wildtype H1 genes. HA1-con protected against three genetically diverse lethal influenza challenges. When mice were challenged with 1934 influenza A/PR/8/34, HA1-con protected 100% of mice while vaccine generated from 2009 A/TX/05/09 only protected 40%. Vaccination with 1934 A/PR/8/34 and 2009 A/TX/05/09 protected 60% and 20% against 1947 influenza A/FM/1/47, respectively, whereas 80% of mice vaccinated with HA1-con were protected. Notably, 80% of mice challenged with 2009 swine flu isolate A/California/4/09 were protected by HA1-con vaccination. These data show that HA1-con in Ad has potential as a rapid and universal vaccine for H1N1 influenza viruses.


Bivariate linkage scan for reading disability and attention-deficit/hyperactivity disorder localizes pleiotropic loci.
There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy. We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs. We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage. Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy.


Epidemiology of acute infections among patients with chronic kidney disease.
The objectives of this review were (1) to review recent literature on the rates, risk factors, and outcomes of infections in patients who had chronic kidney disease (CKD) and did or did not require renal replacement therapy; (2) to review literature on the efficacy and use of selected vaccines for patients with CKD; and (3) to outline a research framework for examining key issues regarding infections in patients with CKD. Infection-related hospitalizations contribute substantially to excess morbidity and mortality in patients with ESRD, and infection is the second leading cause of death in this population. Patients who have CKD and do not require renal replacement therapy seem to be at higher risk for infection compared with patients without CKD; however, data about patients who have CKD and do not require dialysis therapy are very limited. Numerous factors potentially predispose patients with CKD to infection: advanced age, presence of coexisting illnesses, vaccine hyporesponsiveness, immunosuppressive therapy, uremia, dialysis access, and the dialysis procedure. Targeted vaccination seems to have variable efficacy in the setting of CKD and is generally underused in this population. In conclusion, infection is a primary issue when caring for patients who receive maintenance dialysis. Very limited data exist about the rates, risk factors, and outcomes of infection in patients who have CKD and do not require dialysis. Future research is needed to delineate accurately the epidemiology of infections in these populations and to develop effective preventive strategies across the spectrum of CKD severity.


Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: a phase IB study.
Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-four patients with incurable cancers received 2.5, 5, or 10 microgram/kg GM-CSF s.c. either before or concurrently with 1.5 or 3.0 million units/m2/day IL-2. The most common laboratory and clinical side effects included an elevation of the total WBC or eosinophil count due to GM-CSF, and constitutional symptoms due to IL-2. Grade 3 or 4 toxicities included hypotension, thrombocytopenia, elevations in aspartate aminotransferase or bilirubin, renal toxicity, gastrointestinal hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 microgram/kg GM-CSF plus concurrent 3.0 million units IL-2 experienced dose-limiting grade 3 or 4 neurological toxicity, which reversed almost completely. An increase in the serum-soluble IL-2 alpha chain receptor was observed with administration of GM-CSF, IL-2, or the combination. IL-2 therapy enhanced lymphokine-activated killer activity, antibody-dependent cellular cytotoxicity, and lymphocyte activation, with increased CD16 and CD56 expression. GM-CSF increased expression of human leukocyte antigen DR on peripheral blood monocytes and decreased surface expression of CD16 on circulating monocytes and polymorphonuclear cells. Lymphokine-activated killer activity and CD16 expression on monocytes and lymphocytes and CD56 expression on lymphocytes were significantly lower in patients receiving GM-CSF simultaneously with IL-2 than in patients receiving the sequential treatment. Antitumor activity was observed in the lungs of four of eight renal cell carcinoma patients with pulmonary metastases treated with concurrent GM-CSF and IL-2. Although no or minimal shrinkage was observed in the patients' large primary tumors, these results warrant further study. The recommended initial Phase II dose and schedule is 1.25 microgram/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m2/day (4.5 x 10(6) international units/m2/day) IL-2, with subsequent escalation of GM-CSF to 2.5 microgram/kg/day after careful observation for toxicities.


Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study.
Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis. We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14-18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433. Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial. This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence. National Institute for Health Research.


Effect of promoter architecture on the cell-to-cell variability in gene expression.
According to recent experimental evidence, promoter architecture, defined by the number, strength and regulatory role of the operators that control transcription, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect variability in gene expression in a systematic rather than case-by-case fashion. In this article we make such a systematic investigation, based on a microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcriptional output from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can be used to test kinetic models of gene regulation. The emphasis of the discussion is on prokaryotic gene regulation, but our analysis can be extended to eukaryotic cells as well.


Formation of retinal ganglion cell topography during prenatal development.
A fundamental feature of the mammalian visual system is the nonuniform distribution of ganglion cells across the retinal surface. To understand the ontogenetic processes leading to the formation of retinal ganglion cell topography, changes in the regional density of these neurons were studied in relation to ganglion cell loss and the pattern of retinal growth in the fetal cat. Midway through the gestation period, the density of these neurons was only two to three times greater in the area centralis than in the peripheral retina, whereas shortly before birth this central-to-peripheral difference was nearly 20-fold. Age-related changes in the ganglion cell distribution were found not to correspond in time or magnitude to the massive loss of ganglion cells that occurs during prenatal development. Rather, the formation of ganglion cell density gradients can be accounted for by unequal expansion of the growing fetal retina-peripheral regions expand more than the central region, thereby diluting the peripheral density of ganglion cells to a greater degree. Nonuniform growth, in conjunction with differential periods of neurogenesis of the different types of retinal cells, appears to be a dominant factor regulating overall retinal topography. These results suggest that the differential regional expansion of the fetal retina underlies the formation of magnification factors in the developing visual system.


Adolescents' implicit theories predict desire for vengeance after peer conflicts: correlational and experimental evidence.
Why do some adolescents respond to interpersonal conflicts vengefully, whereas others seek more positive solutions? Three studies investigated the role of implicit theories of personality in predicting violent or vengeful responses to peer conflicts among adolescents in Grades 9 and 10. They showed that a greater belief that traits are fixed (an entity theory) predicted a stronger desire for revenge after a variety of recalled peer conflicts (Study 1) and after a hypothetical conflict that specifically involved bullying (Study 2). Study 3 experimentally induced a belief in the potential for change (an incremental theory), which resulted in a reduced desire to seek revenge. This effect was mediated by changes in bad-person attributions about the perpetrators, feelings of shame and hatred, and the belief that vengeful ideation is an effective emotion-regulation strategy. Together, the findings illuminate the social-cognitive processes underlying reactions to conflict and suggest potential avenues for reducing violent retaliation in adolescents.


Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.
Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.


Parental Care in a Stressful World: Experimentally Elevated Cortisol and Brood Size Manipulation Influence Nest Success Probability and Nest-Tending Behavior in a Wild Teleost Fish.
Parental care is an advantageous reproductive behavior, as the fitness of the caregiver is increased through improving the chances of its offspring's survival. Parental care occurs in a variety of teleost fishes. The body size of parental fish and the size of their brood can affect nest abandonment decisions, where compared with smaller fish with smaller broods, larger fish with larger broods typically invest more energy into reproductive events because they have less future reproductive potential. Although essential for basal metabolism and body maintenance functions, when glucocorticoid hormones (e.g., cortisol) are chronically elevated, as can occur during stress, fish may experience impairments in behavior and immune function, leading to compromised health and condition. Anthropogenic stressors during parental care can lead to elevated stress, therefore making it necessary to understand how stress influences an already-challenging period. Using smallmouth bass as a model, a gradient of body sizes, and experimentally manipulated brood size (i.e., reducing large broods and supplementing small broods) and cortisol levels (i.e., elevated via slow-release intraperitoneal cocoa butter implants containing cortisol versus controls), we tested the hypothesis that the reproductive success and parental care behaviors (i.e., aggression, nest tending) of nest-guarding male smallmouth bass are influenced by parental body size, brood size, and cortisol level. Overall, there was a relationship between cortisol treatment and nest success in which larger fish exhibited lower success when cortisol levels were elevated. Brood size had a significant effect on fish-tending behavior, independent of cortisol level and body size. Lending partial support to our hypothesis, the results of this study indicate that the reproductive success of guarding male smallmouth bass is influenced by cortisol level and that tending behavior is affected by brood size.


Beyond CAR T-Cell Therapy: Continued Monitoring and Management of Complications.
Chimeric antigen receptor (CAR) T-cell therapy has recently emerged as a groundbreaking treatment for CD19-expressing hematologic malignancies and received rapid approval by the U.S. Food & Drug Administration. Tisagenlecleucel and axicabtagene ciloleucel are now widely available at CAR T-cell therapy centers around the United States. Many patients have achieved complete response or remission despite failing multiple previous lines of therapy, but some patients endure the severe risks of cytokine release syndrome, neurotoxicity, and other immunologic effects. As more patients receive this therapy, they will present to their primary oncologists in the community setting for continued follow-up. Oncology-trained advanced practitioners must then have a working knowledge of CAR T-cell therapy, its toxicities, and follow-up care. This review presents the CAR T-cell therapy development and infusion process with associated immediate management. In addition, patient assessment and disease monitoring, relevant diagnostics, unique grading systems to CAR T-cell therapy toxicities, indications for hospitalization, infection prophylaxis, and management of nonneutropenic and neutropenic fever are presented.