A profile of spatial abilities in people with Down syndrome.

BACKGROUND: Spatial abilities are fundamental cognitive abilities, have direct applications in daily life, serve as a cognitive foundation for many other complex skills and are used in many specialty jobs. The current study aimed to systematically and comprehensively evaluate the spatial abilities of individuals with Down syndrome (DS) relative to mental ability-matched typically developing (TD) children based on Newcombe and Shipley's double-dimension theoretical framework for classifying spatial abilities. METHODS: Forty adolescents and young adults with DS and 40 TD children completed a nonverbal intelligence test (Raven's), two measures of static-extrinsic skills (water-level task and cart task), two measures of static-intrinsic skills (figure ground and form completion), two measures of dynamic-extrinsic skills (three mountains task and dog task) and two measures of dynamic-intrinsic spatial skills (mental rotation task and block design task). RESULTS: Participants with DS showed reduced performance on two dynamic-intrinsic tasks and one static-extrinsic task (i.e. cart task) relative to TD children. Performances were similar in two dynamic-extrinsic tasks and two static-intrinsic tasks. Analyses of composite accuracy for each spatial category further confirmed deficits in dynamic-intrinsic and static-extrinsic categories for people with DS relative to TD children. CONCLUSIONS: Our results showed an uneven profile of spatial abilities in people with DS relative to ability-matched TD children with particular weaknesses in comprehending and manipulating dynamic-intrinsic and static-extrinsic spatial relations. Furthermore, our research has important clinical implications for more targeted interventions to improve spatial abilities in people with DS.

Anticancer innovative therapy: Highlights from the ninth annual meeting.

The Ninth Annual Conference of "Anticancer Innovative Therapy", organized by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Fondazione IRCCS INT) and hosted by Hotel Michelangelo, was held in Milan on 25 January 2019. Cutting-edge science was presented in two main scientific sessions: i) pre-clinical evidences and new targets, and ii) clinical translation. The Keynote lecture entitled "Cancer stem cells (CSCs): metabolic strategies for their identification and eradication" presented by M. Lisanti, was one of the highlights of the conference. One key concept of the meeting was how the continuous advances in our knowledge about molecular mechanisms in various fields of research (cancer metabolism reprogramming, epigenetic regulation, transformation/invasiveness, and immunology, among others) are driving cancer research towards more effective personalized antineoplastic strategies. Specifically, recent preclinical data on the following topics were discussed: 1. Polycomb group proteins in cancer; 2. A d16HER2 splice variant is a flag of HER2 addiction across HER2-positive cancers; 3. Studying chromatin as a nexus between translational and basic research; 4. Metabolomic analysis in cancer patients; 5. CDK4-6 cyclin inhibitors: clinical activity and future perspectives as immunotherapy adjuvant; and 6. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. In terms of clinical translation, several novel approaches were presented: 1. Developing CAR-T cell therapies: an update of preclinical and clinical development at University of North Carolina; 2. Vγ9Vδ2 T-cell activation and immune suppression in multiple myeloma; 3. Predictive biomarkers for real-world immunotherapy: the cancer immunogram model in the clinical arena; and 4. Mechanisms of resistance to immune checkpoint blockade in solid tumors. Overall, the pre-clinical and clinical findings presented could pave the way to identify novel actionable therapeutic targets to significantly enhance the care of persons with cancer.

Sepsis and Septic Shock Strategies.

Three therapeutic principles most substantially improve organ dysfunction and survival in sepsis: early, appropriate antimicrobial therapy; restoration of adequate cellular perfusion; timely source control. The new definitions of sepsis and septic shock reflect the inadequate sensitivity, specify, and lack of prognostication of systemic inflammatory response syndrome criteria. Sequential (sepsis-related) organ failure assessment more effectively prognosticates in sepsis and critical illness. Inadequate cellular perfusion accelerates injury and reestablishing perfusion limits injury. Multiple organ systems are affected by sepsis and septic shock and an evidence-based multipronged approach to systems-based therapy in critical illness results in improve outcomes.

Phenotypic analysis of familial breast cancer: comparison of BRCAx tumors with BRCA1-, BRCA2-carriers and non-familial breast cancer.

AIMS: Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. METHODS: We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. RESULTS: We found non-familial cases to be more likely to be ER positive (P = 0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors (P = 0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive (P = 0.001) and HER2 positive (P = 0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive (P = 0.02) but more likely to be HER2 positive (P = 0.021) as compared with BRCA2 tumors. CONCLUSION: Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention.

Transcriptional regulation of cellular senescence.

Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. This review focuses on the role of transcriptional regulators in the control of cellular senescence, explores how their function is perturbed in cancer and discusses the potential to harness this knowledge for future cancer therapies.

Regulation of stem cell differentiation by histone methyltransferases and demethylases.

The generation of different cell types from stem cells containing identical genetic information and their organization into tissues and organs during development is a highly complex process that requires defined transcriptional programs. Maintenance of such programs is epigenetically regulated and the factors involved in these processes are often essential for development. The activities required for cell-fate decisions are frequently deregulated in human tumors, and the elucidation of the molecular mechanisms that regulate these processes is therefore important for understanding both developmental processes and tumorigenesis.

A model of solute transport through stratum corneum using solute capture and release.

A one-dimensional model of solute transport through the stratum corneum is presented. Solute is assumed to diffuse through lipid bi-layers surrounding impermeable corneocytes. Transverse diffusion (perpendicular to the skin surface) through lipids separating adjacent corneocytes, is modeled in the usual way. Longitudinal diffusion (parallel to the skin surface) through lipids between corneocyte layers, is modeled as temporary trapping of solute, with subsequent release in the transverse direction. This leads to a linear equation for one-dimensional transport in the transverse direction. The model involves an arbitrary function whose precise form is uncertain. For a specific choice of this function, closed form expressions for the Laplace transform of solute out-flux at the inner boundary, and for the time lag are obtained in the case that a constant solute concentration is maintained at the outer skin surface, with the inner boundary of the stratum corneum kept at zero concentration, and with the stratum corneum initially free of solute.

Measuring patient safety climate: a review of surveys.

OBJECTIVE: Five years ago the Institute of Medicine recommended improving patient safety by addressing organizational cultural issues. Since then, surveys measuring a patient safety climate considered predictive of health outcomes have begun to emerge. This paper compares the general characteristics, dimensions covered, psychometrics performed, and uses in studies of patient safety climate surveys. METHODS: Systematic literature review. RESULTS: Nine surveys were found that measured the patient safety climate of an organization. All used Likert scales, mostly to measure attitudes of individuals. Nearly all covered five common dimensions of patient safety climate: leadership, policies and procedures, staffing, communication, and reporting. The strength of psychometric testing varied. While all had been used to compare units within or between hospitals, only one had explored the association between organizational climate and patient outcomes. CONCLUSIONS: Patient safety climate surveys vary considerably. Achievement of a culture conducive to patient safety may be an admirable goal in its own right, but more effort should be expended on understanding the relationship between measures of patient safety climate and patient outcomes.

E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.

The retinoblastoma protein (pRB) and its two relatives, p107 and p130, regulate development and cell proliferation in part by inhibiting the activity of E2F-regulated promoters. We have used high-density oligonucleotide arrays to identify genes in which expression changed in response to activation of E2F1, E2F2, and E2F3. We show that the E2Fs control the expression of several genes that are involved in cell proliferation. We also show that the E2Fs regulate a number of genes involved in apoptosis, differentiation, and development. These results provide possible genetic explanations to the variety of phenotypes observed as a consequence of a deregulated pRB/E2F pathway.

Reassembly and protection of small nuclear ribonucleoprotein particles by heat shock proteins in yeast cells.

The process of mRNA splicing is sensitive to in vivo thermal inactivation, but can be protected by pretreatment of cells under conditions that induce heat-shock proteins (Hsps). This latter phenomenon is known as "splicing thermotolerance". In this article we demonstrate that the small nuclear ribonucleoprotein particles (snRNPs) are in vivo targets of thermal damage within the splicing apparatus in heat-shocked yeast cells. Following a heat shock, levels of the tri-snRNP (U4/U6.U5), free U6 snRNP, and a pre-U6 snRNP complex are dramatically reduced. In addition, we observe multiple alterations in U1, U2, U5, and U4/U6 snRNP profiles and the accumulation of precursor forms of U4- and U6-containing snRNPs. Reassembly of snRNPs following a heat shock is correlated with the recovery of mRNA splicing and requires both Hsp104 and the Ssa Hsp70 family of proteins. Furthermore, we correlate splicing thermotolerance with the protection of a subset of snRNPs by Ssa proteins but not Hsp104, and show that Hsp70 directly associates with U4- and U6-containing snRNPs in splicing thermotolerant cells. In addition, our results show that Hsp70 plays a role in snRNP assembly under normal physiological conditions.

Interconnected-tubes model of hepatic elimination: steady-state considerations.

In the interconnected-tubes model of hepatic transport and elimination, intermixing between sinusoids was modelled by the continuous interchange of solutes between a set of parallel tubes. In the case of strongly interconnected tubes and for bolus input of solute, a zeroth-order approximation led to the governing equation of the dispersion model. The dispersion number was expressed for the first time in terms of its main physiological determinants: heterogeneity of flow and density of interconnections. The interconnected-tubes model is now applied to steady-state hepatic extraction. In the limit of strong interconnections, the expression for output concentrations is predicted to be similar in form to those predicted by the distributed model for a narrow distribution of elimination rates over sinusoids, and by the dispersion model in the limit of a small dispersion number D(N). More generally, the equations for the predicted output concentrations can be expressed in terms of a dimensionless 'heterogeneity number'H(N), which characterizes the combined effects of variations in enzyme distribution and flow rates between different sinusoids, together with the effects of interconnections between sinusoids. A comparative analysis of the equations for the dispersion and heterogeneity numbers shows that the value of H(N)can be less than, greater than or equal to the value of D(N)for a correlation between distributions of velocities and elimination rates over sinusoids, anticorrelation between them, and when all sinusoids have the same elimination rate, respectively. Simple model systems are used to illustrate the determinants of H(N)and D(N).

Streamlining nutritional care for the physician's office.

OBJECTIVE: Nutritional care needs are overlooked in clinical practice. We review nutritional needs and describe an approach for improving nutritional care in clinical practice. DESIGN: Data from a controlled trial and several population cohorts. SETTING: Primary care practices and a population survey in New Hampshire and Vermont, USA. SUBJECTS: The controlled trial involved 1651 persons aged 70+years. The cohorts include information from 1879 persons aged 12+. INTERVENTION: All patients completed standard surveys which included information about nutritional needs. 22 practices participated in the trial. RESULTS: The higher the BMI, the less healthy the population. 15 30% of patients report problems or concerns with eating/weight and nutrition. Patients with problems or concerns are often bothered by other health and social problems. Patients who have productive interactions with clinicians have improved nutritional care and are more likely to report help with eating problems (68% vs 86%; Odds ratio 5.0 (95% CI: 0.9-27.0). CONCLUSIONS: Nutritional issues are common and complex. A productive provider-patient interaction can improve the nutritional care of patients. Essential elements for a productive interaction include an informed, educated patient and a provider (or clinical team) prepared to assess and manage the broad range of issues that are important to the patient. Technology facilitates necessary feedback between patient and provider.

Long-term consequences of adolescent health behaviors: implications for adolescent health services.

The authors discuss the evidence supporting the effectiveness of adolescent preventive services to influence health outcomes, the magnitude of the long-term consequences of adolescent health-compromising behaviors, and their implications for health policies. Particular attention is given to the contribution that behaviors participated in or begun during adolescence have on long-term health, including cancer and heart disease. They postulate the health benefits that might accrue from the widespread implementation of comprehensive adolescent preventive services, assuming a conservative estimate of effectiveness, could be significant.

A computerized school-based health assessment with rapid feedback to improve adolescent health.

Adolescent health problems are often undetected in physicians' offices. The Dartmouth Primary Care Cooperative Information Project has developed a validated and reliable approach to identify adolescent health problems and initiate education in a school setting. A self-administered, anonymous, 26-item questionnaire was given to 204 students in a rural high school. Responses were scanned into PC-based software. Within one working day students were given individualized letters identifying their problem health issues as detected by the questionnaire and recommendations for education. Ninety-nine percent of students participated. Six weeks later 49% of a sample of 41 students reported reading the information and 50% planned to change behavior. This standardized, validated strategy of adolescent health assessment, feedback, and education was feasible for use in schools. The school responded to the data by employing a psychologist to address mental health needs.

Interconnected-tubes model of hepatic elimination.

The distributed-tubes model of hepatic elimination is extended to include intermixing between sinusoids, resulting in the formulation of a new, interconnected-tubes model. The new model is analysed for the simple case of two interconnected tubes, where an exact solution is obtained. For the case of many strongly-interconnected tubes, it is shown that a zeroth-order approximation leads to the convection-dispersion model. As a consequence the dispersion number is expressed, for the first time, in terms of its main physiological determinants: heterogeneity of flow and density of interconnections between sinusoids. The analysis of multiple indicator dilution data from a perfused liver preparation using the simplest version of the model yields the estimate 10.3 for the average number of interconnections. The problem of boundary conditions of the dispersion model is considered from the viewpoint that the dispersion-convection equation is a zeroth-order approximation to the equations for the interconnected-tubes model.

Metabolite mean transit times in the liver as predicted by various models of hepatic elimination.

Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver. Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tanks-in-series models are between the predictions of the tank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MTT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.

Sexual assault: review of a national model protocol for forensic and medical evaluation. New Hampshire Sexual Assault Medical Examination Protocol Project Committee.

A national hospital/community model protocol was developed for the forensic and medical examination of victims of sexual assault. This review is designed to assist states in the development of sexual assault protocols. Controversial issues were addressed, including the collection of hair evidence, the importance of semen, mandatory reporting, pregnancy testing and prophylaxis, and sexually transmitted diseases including human immunodeficiency virus. The current role of DNA profiling is reviewed. These issues at the interface of medicine, forensic science, victim advocacy, and the law are analyzed. Representatives of the medical, legal, law enforcement, victim advocacy, and forensic science communities contributed to the development of the protocols at the national and state levels. The importance of a collaborative effort is emphasized. The broad protocol goals are to minimize the physical and psychological trauma to the victim while maximizing the probability of collecting and preserving physical evidence for potential use in the legal system.

Flux ratio theorems for nonstationary membrane transport with temporary capture of tracer.

It has been shown recently that the ratio of unidirectional tracer fluxes, passing in opposite directions through a membrane which has transport properties varying arbitrarily with the distance from a boundary, is independent of time from the very first appearance of the two outfluxes from the membrane. This surprising proposition has been proved for boundary conditions defining standard unidirectional fluxes, and then generalized to classes of time-dependent boundary conditions. The operational meaning of all the resulting theorems is that when any of them appear to be refuted experimentally, the presence of more than one parallel transport pathway (that is, of membrane heterogeneity transverse to the direction of transport) can be inferred and analyzed. Recent experimental data have been interpreted accordingly. However, the proofs of the theorems given so far have not taken into account the possibility of temporary capture of tracer at sites fixed in the membrane (including also entrances to microscopic culs-de-sac). The possible presence of such a process, which would not affect fluxes in the steady state, left a fundamental gap in the aforementioned inferences. It is shown here that all the theorems previously proved for the flux ratio under unsteady conditions remain valid when temporary capture of tracer is admitted, no matter how the rate of capture, and the probability distribution of residence times of tracer at capture sites, may depend on the distance from a membrane boundary. The validity of the aforementioned inferences from observed time-dependence of the flux ratio is thereby extended to a much wider class of membrane transport processes.

Asymptotic forms of tracer clearance curves: theory and applications of improved extrapolations.

Tracer clearance curves are conventionally extrapolated beyond times of observation by using monoexponential asymptotic forms. The inadequacy of the resulting predictions, especially as to the mean transit time and quantities derived from it, has been previously demonstrated experimentally. Here improvements in extrapolations and in the resulting predictions are derived theoretically and tested on previously published data, venous as well as externally recorded. First, secure lower bounds on the mean transit times are constructed, and shown to be much higher than conventional outright estimates for venous data (twice as high in some cases). Next, new asymptotic forms of tracer clearance curves from kinetically heterogeneous systems are derived; they are not monoexponential, but they are as robust, contain as few parameters and are as easily connected to data. It is shown theorectically that for real organs these new asymptotic forms should extrapolate and predict better than monoexponentials, and this is demonstrated on previously published venous data from perfused muscle. In particular, the resulting outright predictions of mean transit times are substantially better than the best lower bounds. Furthermore, a correction is derived to the standard estimate of the rate of regional cerebral blood flow. In an application to previously published data recorded externally, that correction reduces the estimated flow rate by 4%.