Karger Publishers (Switzerland)

BACKGROUND/AIMS: Increasing public awareness of obesity genetics could have beneficial or harmful effects on overweight individuals. This study examined the impact of genetic information on weight-related cognitions as well as interest in personalized genetic information about obesity among overweight individuals. METHODS: Online survey respondents (n = 655) were randomly assigned to read either genetic, gene-environment, or nongenetic obesity causal information. Fifty-two percent of the participants were female, 82.4% were White, 45% had an annual income of USD <40,000, and the mean BMI was 32.5. Internalized weight stigma was measured using the Weight Bias Internalization Scale. RESULTS: Participants in the genetic and gene-environment conditions were more likely to believe genetics increase obesity risk than participants in the nongenetic condition (both p < 0.05); however, they did not differ regarding internalized weight stigma. Sixty-four percent of the participants expressed interest in receiving personalized genetic information about their obesity risk. CONCLUSION: Dissemination of information about obesity genetics may have neither a beneficial nor a harmful impact on how overweight individuals perceive themselves. Some overweight individuals may be interested in receiving personalized genetic information. The actual effects of obesity genetic information being incorporated into public health messages and of personalized genetic information on obesity prevention and treatment interventions remain to be seen.

Within the context of poorer patient outcomes and rising healthcare costs, we need to better understand why many patients do not engage fully with their treatment plan. Movement away from talking about "compliance" towards "adherence" and "concordance" is evidence of a recognition that this is a two-way process. Whilst healthcare professionals expect patients to engage in treatment, equally, patients have expectations (whether positive or negative) of their treatment and their need for engagement. There is a need for an effective method that can specifically target those interventions that will provide the most benefit to individual patients and which, crucially, is easy and inexpensive to administer in everyday practice and widely applicable. Rubin's Four Tendencies model identifies a patient's "response to outer and inner expectations" as a key factor in adherence. The model therefore provides an opportunity to test such a targeted, patient-specific strategy and we present a call to action for research in this area.

Autophagy is a highly conserved degradative pathway that has rapidly emerged as a critical component of immunity and host defense. Studies have implicated autophagy genes in restricting the replication of a diverse array of pathogens, including bacteria, viruses and protozoans. However, in most cases, the in vivo role of antimicrobial autophagy against pathogens has been undefined. Drosophila provides a genetically tractable model system that can be easily adapted to study autophagy in innate immunity, and recent studies in flies have demonstrated that autophagy is an essential antimicrobial response against bacteria and viruses in vivo. These findings reveal striking conservation of antimicrobial autophagy between flies and mammals, and in particular, the role of pathogen-associated pattern recognition in triggering this response. This review discusses our current understanding of antimicrobial autophagy in Drosophila and its potential relevance to human immunity.

Evidence-based recommendations on the clinical use of cardiopulmonary exercise testing (CPET) in lung and heart disease are presented, with reference to the assessment of exercise intolerance, prognostic assessment and the evaluation of therapeutic interventions (e.g. drugs, supplemental oxygen, exercise training). A commonly used grading system for recommendations in evidence-based guidelines was applied, with the grade of recommendation ranging from A, the highest, to D, the lowest. For symptom-limited incremental exercise, CPET indices, such as peak O(2) uptake (V'O(2)), V'O(2) at lactate threshold, the slope of the ventilation-CO(2) output relationship and the presence of arterial O(2) desaturation, have all been shown to have power in prognostic evaluation. In addition, for assessment of interventions, the tolerable duration of symptom-limited high-intensity constant-load exercise often provides greater sensitivity to discriminate change than the classical incremental test. Field-testing paradigms (e.g. timed and shuttle walking tests) also prove valuable. In turn, these considerations allow the resolution of practical questions that often confront the clinician, such as: 1) "When should an evaluation of exercise intolerance be sought?"; 2) "Which particular form of test should be asked for?"; and 3) "What cluster of variables should be selected when evaluating prognosis for a particular disease or the effect of a particular intervention?"

OBJECTIVE: Patients diagnosed with colorectal cancer before the age of 50 years are recommended for Lynch syndrome (LS) testing according to current clinical guidelines. However, many patients are not identified because of the stringent guidelines on existing diagnostic criteria. The aim of this analysis was to evaluate the ability of existing criteria to adequately ascertain patients appropriate for LS genetic testing. METHOD: To determine whether existing clinical diagnostic criteria underascertain individuals who would be appropriate candidates for hereditary cancer risk assessment, we stratified the detection rate of deleterious mismatch repair (MMR) mutations in 9,109 patients with a personal history of colorectal cancer who were diagnosed between the ages of 30 and 74 years with little or no family history suggestive of LS by 5-year age-at-detection intervals. RESULTS: There was little difference in the aggregate positive mutation rate in individuals diagnosed between the ages of 50 and 59 years compared to the positive mutation rate in patients diagnosed before the age of 50 years. CONCLUSION: These results suggest that cancer diagnosis under the age of 50 years is an insufficiently sensitive predictor of hereditary cancer susceptibility.

By the year 2050, individuals over the age of 65 years will comprise 20% of the US population. Loss of muscle mass and strength is common in this age group and it is associated with increased dependence, frailty and mortality. Sarcopenia, defined as the loss of muscle mass and function associated with aging, and cachexia, defined as weight loss due to an underlying illness, are muscle wasting disorders of particular relevance in the aging population, but they go largely unrecognized. In this review we highlight the common pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, the factors unique to each condition and means of diagnosing and differentiating them clinically. Therapeutic options including exercise, nutritional therapy, androgens and growth hormone as well as their practical limitations are discussed. We also shed light on newer agents being developed as potential therapeutic options for wasting diseases.

Cervical ultrasound scanning (US) is considered a key examination, by all major thyroid and endocrine specialist societies for the postoperative follow-up of thyroid cancer patients to assess the risk of recurrence. Neck US imaging is readily available, non-invasive, relatively easy to perform, cost-effective, and can guide diagnostic and therapeutic procedures with low complication rates. Its main shortcoming is its operator-dependency. Because of the pivotal role of US in the care of thyroid cancer patients, the European Thyroid Association convened a panel of international experts to review technical aspects, indications, results, and limitations of cervical US in the initial staging and follow-up of thyroid cancer patients. The main aim is to establish guidelines for both a cervical US scanning protocol and US-guided diagnostic and therapeutic procedures in patients with thyroid cancer. This report presents (1) standardization of the US scanning procedure, techniques of US-guided fine-needle aspiration, and reporting of findings; (2) definition of criteria for classification of malignancy risk based on cervical US imaging characteristics of neck masses and lymph nodes; (3) indications for US-guided fine-needle aspiration and for biological in situ assessments; (4) proposal of an algorithm for the follow-up of thyroid cancer patients based on risk stratification following histopathological and cervical US findings, and (5) discussion of the potential use of US-guided localization and ablation techniques for locoregional thyroid metastases.

The purpose of this perspective is to describe a critical advance in understanding how immune responses work. Macrophages are required for all animal life: 'Inhibit' type macrophages in all animals (called M1) can rapidly kill pathogens, and are thus the primary host defense, and 'Heal' type macrophages (M2) routinely repair and maintain tissue integrity. Macrophages perform these activities in all animals without T cells, and also in T cell-deficient vertebrates. Although adaptive immunity can amplify macrophage polarization, the long-held notion that macrophages need to be 'activated' or 'alternatively activated' by T cells is incorrect; indeed, immunology has had it backward. M1/M2-type macrophages necessarily direct T cells toward Th1- or Th2-like activities, respectively. That such macrophage-innate activities are the central directing element in immune responses is a dramatic change in understanding how immune systems operate. Most important, this revelation is opening up whole new approaches to immunotherapy. For example, many modern diseases, such as cancer and atherosclerosis, may not display 'foreign' antigens. However, there are clear imbalances in M1/M2-type responses. Correcting such innate imbalances can result in better health. Macrophages are the chicken and the egg of immunity.

Several histopathological features are found more frequently in placentas from pregnancies complicated by fetal growth restriction (FGR), including villous infarction, maternal vascular changes and villous morphological alterations, although around one quarter of placentas associated with FGR lack any morphological abnormality on routine examination. Since similar changes may also affect clinically uncomplicated pregnancies, the positive predictive value of such findings for pathological FGR in an unselected case remains low. However, the pattern of placental pathologies varies with clinical subgroup. The combination of placental bed and parenchymal lesions in FGR with abnormal uterine artery Doppler velocimetry is essentially identical to preterm pre-eclampsia (PET), and there is an association between FGR with abnormal umbilical artery Doppler findings and lesions of fetal stem arteries and terminal villous hypovascularity. Conversely, placentas from pregnancies complicated by PET or FGR presenting at or near term have a significantly lower frequency of histological abnormalities compared to early-onset disease and absence of a distinctive biochemical profile. The histological placental findings in FGR are therefore varied, from morphologically unremarkable through to severe uteroplacental vasculopathy, with no single pathological feature associated with high sensitivity or specificity. Severe early-onset FGR, overlapping with severe early-onset PET, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective extravillous trophoblast invasion, and its consequences. Late-onset FGR probably represents a more heterogeneous group with less characteristic histological changes. Future research using histopathological assessment of aggregated data from multiple studies into larger datasets with centralised pathology review will allow delineation of distinctive clinicopathological associations and further understanding of pathophysiology.

A novel cDNA, IA-2beta, was isolated from a mouse neonatal brain library. The predicted protein sequence revealed an extracellular domain, a transmembrane region, and an intracellular domain. The intracellular domain is 376 amino acids long and 74% identical to the intracellular domain of IA-2, a major autoantigen in insulin-dependent diabetes mellitus (IDDM). A partial sequence of the extracellular domain of IA-2beta indicates that it differs substantially (only 26% identical) from that of IA-2. Both molecules are expressed in islets and brain tissue. Forty-six percent (23 of 50) of the IDDM sera but none of the sera from normal controls (0 of 50) immunoprecipitated the intracellular domain of IA-2beta. Competitive inhibition experiments showed that IDDM sera have autoantibodies that recognize both common and distinct determinants on IA-2 and IA-2beta. Many IDDM sera are known to immunoprecipitate 37-kDa and 40-kDa tryptic fragments from islet cells, but the identity of the precursor protein(s) has remained elusive. The current study shows that treatment of recombinant IA-2beta and IA-2 with trypsin yields a 37-kDa fragment and a 40-kDa fragment, respectively, and that these fragments can be immunoprecipitated with diabetic sera. Absorption of diabetic sera with unlabeled recombinant IA-2 or IA-2beta, prior to incubation with radiolabeled 37-kDa and 40-kDa tryptic fragments derived from insulinoma or glucagonoma cells, blocks the immunoprecipitation of both of these radiolabeled tryptic fragments. We conclude that IA-2beta and IA-2 are the precursors of the 37-kDa and 40-kDa islet cell autoantigens, respectively, and that both IA-2 and IA-2beta are major autoantigens in IDDM.

Infancy and childhood represent a time of unparalleled physical growth and cognitive development. In order for infants and children to reach their linear and neurological growth potential, they must be able to reliably and safely consume sufficient energy and nutrients. Swallowing difficulties (dysphagia) in pediatric populations can have a detrimental effect on dietary intake and, thus, growth and development. As a result, it is imperative to accurately identify and appropriately manage dysphagia in pediatric populations. This article provides an overview of dysphagia in children, as well as common causes of childhood swallowing difficulties, populations at risk for pediatric dysphagia, techniques used to assess swallowing in pediatric patients, and the current treatment options available for infants and children with dysphagia.

BACKGROUND: The kinship2 package is restructured from the previous kinship package. Existing features are now enhanced and new features added for handling pedigree objects. METHODS: Pedigree plotting features have been updated to display features on complex pedigrees while adhering to pedigree plotting standards. Kinship matrices can now be calculated for the X chromosome. Other methods have been added to subset and trim pedigrees while maintaining the pedigree structure. CONCLUSION: We make the kinship2 package available for R on the Contributed R Archives Network (CRAN), where data management is built-in and other packages can use the pedigree object.

Therapies aimed at manipulating the microcirculation require the ability to control angiogenesis, defined as the sprouting of new capillaries from existing vessels. Blocking angiogenesis would be beneficial in many pathologies (e.g. cancer, retinopathies and rheumatoid arthritis). In others (e.g. myocardial infarction, stroke and hypertension), promoting angiogenesis would be desirable. We know that vascular pericytes elongate around endothelial cells (ECs) and are functionally associated with regulating vessel stabilization, vessel diameter and EC proliferation. During angiogenesis, bidirectional pericyte-EC signaling is critical for capillary sprout formation. Observations of pericytes leading capillary sprouts also implicate their role in EC guidance. As such, pericytes have recently emerged as a therapeutic target to promote or inhibit angiogenesis. Advancing our basic understanding of pericytes and developing pericyte-related therapies are challenged, like in many other fields, by questions regarding cell identity. This review article discusses what we know about pericyte phenotypes and the opportunity to advance our understanding by defining the specific pericyte cell populations involved in capillary sprouting.

Fetal anemia is a serious complication in pregnancy and associated with perinatal mortality and morbidity. During 25 years of worldwide experience with intravascular intrauterine blood transfusion, a variety of indications have been described. Intrauterine transfusion (IUT) treatment is considered most successful for fetal anemia due to red cell alloimmunization. Moreover, the use of this procedure has also been reported in pregnancies with parvovirus B19 infection, fetomaternal hemorrhage and placental chorioangiomas, for example. This review focuses on the current indications of intrauterine blood transfusions. In addition, we describe the potential complications of IUT treatment.

The identification and application of biomarkers in the clinical and medical fields has an enormous impact on society. The increase of digital devices and the rise in popularity of health-related mobile apps has produced a new trove of biomarkers in large, diverse, and complex data. However, the unclear definition of digital biomarkers, population groups, and their intersection with traditional biomarkers hinders their discovery and validation. We have identified current issues in the field of digital biomarkers and put forth suggestions to address them during the DayOne Workshop with participants from academia and industry. We have found similarities and differences between traditional and digital biomarkers in order to synchronize semantics, define unique features, review current regulatory procedures, and describe novel applications that enable precision medicine.

BACKGROUND: The cause of cerebral small vessel disease is not fully understood, yet it is important, accounting for about 25% of all strokes. It also increases the risk of having another stroke and contributes to about 40% of dementias. Various processes have been implicated, including microatheroma, endothelial dysfunction and inflammation. A previous review investigated endothelial dysfunction in lacunar stroke versus mostly non-stroke controls while another looked at markers of inflammation and endothelial damage in ischaemic stroke in general. We have focused on blood markers between clinically evident lacunar stroke and other subtypes of ischaemic stroke, thereby controlling for stroke in general. SUMMARY: We systematically assessed the literature for studies comparing blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-stroke controls or other ischaemic stroke subtypes. We assessed the quality of included papers and meta-analysed results. We split the analysis on time of blood draw in relation to the stroke. We identified 1,468 full papers of which 42 were eligible for inclusion, including 4,816 ischaemic strokes, of which 2,196 were lacunar and 2,500 non-stroke controls. Most studies subtyped stroke using TOAST. The definition of lacunar stroke varied between studies. Markers of coagulation/fibrinolysis (tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), fibrinogen, D-dimer) were higher in lacunar stroke versus non-stroke although fibrinogen was no different to non-stroke in the acute phase. tPA and PAI were no different between lacunar and non-lacunar stroke. Fibrinogen and D-dimer were significantly lower in lacunar stroke compared to other ischaemic strokes, both acutely and chronically. Markers of endothelial dysfunction (homocysteine, von Willebrand Factor (vWF), E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM), vascular cellular adhesion molecule-1 (VCAM)) were higher or had insufficient or conflicting data (P-selectin, VCAM) in lacunar stroke versus non-stroke. Compared to other ischaemic stroke subtypes, homocysteine did not differ in lacunar stroke while vWF was significantly lower in lacunar stroke acutely [atherothrombotic standardized mean difference, SMD, -0.34 (-0.61, -0.08); cardioembolic SMD -0.38 (-0.62, -0.14)], with insufficient data chronically. Markers of inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)) were higher in lacunar stroke versus non-stroke, although there were no studies measuring TNF-α chronically and the sole study measuring IL-6 chronically showed no difference between lacunar stroke and non-stroke. Compared to other ischaemic stroke subtypes, there was no difference (CRP) or insufficient or conflicting data (TNF-α) to lacunar stroke. IL-6 was significantly lower [atherothrombotic SMD -0.37 (-0.63, -0.10); cardioembolic SMD -0.52 (-0.82, -0.22)] in lacunar stroke acutely, with insufficient data chronically. KEY MESSAGES: Lacunar stroke is an important stroke subtype. More studies comparing lacunar stroke to non-lacunar stroke specifically, rather than to non-stroke controls, are needed. Prospective studies with measurements taken well after the acute event are more likely to be helpful in determining pathogenesis. The available data in this review were limited and do not exclude the possibility that peripheral inflammatory processes including endothelial dysfunction are associated with lacunar stroke and cerebral small vessel disease.

In the year 2011, 6.9 million children under the age of 5 years died worldwide, one third of them related to increased susceptibility to illnesses due to undernutrition. An estimated 178 million children under 5 years are stunted, 55 million are wasted, and 19 million of these are severely affected and are at a higher risk of premature death, the vast majority being from sub-Saharan Africa and South-Central Asia. Globally, over 2 billion people are at risk for vitamin A, iodine, and/or iron deficiency. Other micronutrient deficiencies of public health concern include zinc, folate, and the B vitamins. The risk factors for undernutrition include low birth weight, inadequate breastfeeding, improper complementary feeding, and recurrent infections. Infectious diseases often coexist with micronutrient deficiencies and exhibit complex interactions leading to the vicious cycle of malnutrition and infections. Diarrhea along with the poor selection and intake of complementary food are the major contributors to undernutrition. Possible strategies to combat malnutrition include promotion of breastfeeding, dietary supplementation of micronutrients, prevention of protein-energy malnutrition, and improvement in the standard of preparation and hygiene of available weaning foods. The universal coverage with the full package of these proven interventions at observed levels of program effectiveness could prevent about one quarter of child deaths under 36 months of age and reduce the prevalence of stunting at 36 months by about one third. The median coverage rate of interventions along the continuum of care for Countdown countries has however been ≥80% for vaccination and vitamin A supplementation. However, for several interventions, including early initiation and exclusive breastfeeding below 6 months of age and case management of childhood illnesses, the median coverage rate hovers at or below 50%. This suggests that interventions requiring strong health systems or behavior change appear to be stalled and need to be re-examined to find more effective ways of delivery.

BACKGROUND: In plants, the final stage of organ development is termed senescence. This is a deterioration process that leads to the decay of tissues and organs, and that, in the case of annual, biennial and/or monocarpic plants, leads to the death of the plant itself. The main function of leaf senescence is nutrient recycle and, since this confers an adaptive advantage, it can be considered an evolutionary selected process. Multiple developmental and environmental signals control senescence, and among them plant hormones are understood to play important roles. In particular, the function of cytokinins and ethylene in senescence has been studied for decades, but it is only since Arabidopsis thaliana was established as a model organism for molecular genetic studies that the underlying molecular and biochemical events have begun to be elucidated. METHODS: In this review, we summarize the present understanding of the role of hormones in the developmental control of leaf senescence in plants and in particular highlight recent studies which address its molecular control. RESULTS: Important findings which connect hormone action to developmental senescence were made in the past few years. For example, it was shown that ethylene activity in natural, age-dependent leaf senescence is conferred by the regulatory function of EIN2, an ethylene-signaling component, in the control of the transcription factor oresara 1 (ORE1), which regulates a large set of senescence-associated genes in their expression. ORE1 mRNA abundance is regulated by the microRNA miR164, which in aging plants is degraded in an EIN2-dependent manner, and it is interesting that another microRNA also governs the hormonal control of senescence. miR319 regulates mRNA abundance of a class of transcription factors which control the expression of LOX2 (lipoxygenase 2), a key enzyme in the JA biosynthetic pathway, and thereby regulates JA homeostasis in senescing leaves. CONCLUSION: Reverse and forward genetics have facilitated the elucidation of molecular mechanisms involved in the control of leaf senescence by phytohormones. Studies initiated on the interactions between the different hormonal pathways that control leaf senescence should improve our knowledge in the future.

inal symptoms at the same intensity as before treatment, entailing a return of the same episode and a new episode of illness, respectively [6, 9] . When treatment with a CNS drug is discontinued, patients can experience classic new withdrawal symptoms, rebound and/or persistent postwithdrawal disorders, or relapse/recurrence of the original illness [6, 9, 14] . New and rebound symptoms can occur for up to 6 weeks after drug withdrawal, depending on the drug elimination half-life [2, 3] , while persistent postwithdrawal or tardive disorders associated with longlasting receptor changes may persist for more than 6 weeks after drug discontinuation. Initial withdrawal symptoms from CNS drugs have been reported to be more frequent and severe when high-potency drugs and drugs with a short elimination half-life have been used [9, 10] . CNS drugs with a shorter elimination half-life and rapid onset of action also carry a higher risk of dependency and high-dose use [9, 10] . Withdrawal symptoms can be relatively short-lasting, lasting for a few hours to a few weeks with complete recovery, while others may persist and last for several months [1, 15, 16] . Fava et al. [1] have proposed using the terminology ‘withdrawal syndrome’ to replace the term ‘discontinuation syndrome’, which has been most often used to describe SSRI withdrawal. They have recommended the Selective serotonin reuptake inhibitors (SSRIs) are widely used in clinical practice, and have advanced the treatment of depression and other mental disorders. However, more studies are needed on the effects of decreasing and discontinuing these medications after their long-term use [1] . Withdrawal symptoms may occur with all SSRIs and serotonin-noradrenaline reuptake inhibitors (SNRIs) [1] , similarly to other CNS drugs, including benzodiazepines [2–4] and antipsychotics [5, 6] . Withdrawal from SSRIs and other CNS drugs produces psychiatric symptoms that can be confounded with true relapse or recurrence of the original illness [1, 2, 7] . When discontinuing or decreasing SSRIs, withdrawal symptoms must be identified to avoid prolonging treatment or giving unnecessarily high doses [6, 8] . Different types of syndromes have been described with the withdrawal from SSRIs and other CNS drug classes, including benzodiazepines, antipsychotics, antidepressants, opiates, barbiturates, and alcohol: (1) new withdrawal symptoms (classic withdrawal symptoms from CNS drugs) [1, 4–6, 9–12] , (2) rebound [2, 6, 9, 13–16] , and (3) persistent postwithdrawal disorders [7, 17, 18] ( table 1 ). These types of withdrawal need to be differentiated from relapse and recurrence of the original illness. Relapse and recurrence are the gradual return of the origReceived: October 12, 2014 Accepted after revision: January 6, 2015 Published online: February 21, 2015

The effects of reperfusion on the myocardial accumulation of neutrophils and their role in the extent of injury were investigated in a canine preparation with a 3 hr coronary occlusion followed by 21 hr of reperfusion. The left anterior descending coronary artery (LAD) was permanently occluded in group 1 and reperfused after 3 hr in four others (groups 2 to 5). All but group 5 received lidocaine (1 mg/min over 8 hr). A critical stenosis was produced and left in place at reperfusion only in group 2. In groups 1 and 2, 111In-labeled autologous neutrophils were injected at the time of coronary occlusion. Group 4 animals were rendered leukopenic 2 hr before the coronary ligature and throughout the experiment by injection of an antineutrophil rabbit serum. Quantification of the radioactivity by digitized scintigraphy of the heart slices revealed an 80% (p less than .05) increase in neutrophil accumulation in the infarct region after reperfusion (group 2) as compared with permanent occlusion (group 1). Gamma counting of myocardial tissue samples showed that the neutrophil accumulation ratio in the subendocardial central zone of the infarct was increased five times (p less than .05) by reperfusion, whereas no difference was evident in the subepicardium. Infarct size and myocardial area at risk were not statistically different among the five groups. However LAD flow in the leukopenic group (group 4) was significantly higher (p less than .05) 30 min after reperfusion (40.0 +/- 5 ml/min) when compared with the preocclusion value (21.7 +/- 4 ml/min). In contrast, in a parallel experiment without leukopenia (group 3), LAD flow after reperfusion did not differ from the preocclusion value.(ABSTRACT TRUNCATED AT 250 WORDS)